Study Database
Find peer-reviewed studies categorized by condition to learn more about your diagnosis and the real world outcomes of stem cell therapy. This database will be periodically updated with new studies as they are published .
Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) – induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.
Phase I Trial of Repeated Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis
Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 106 cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients’ disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period.
ALS Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside
Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.
Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Patients show both motor and extra-motor symptoms. A cure is not available at this time, and the disease leads to death within 3–5 years, mainly due to respiratory failure. Stem cell therapy is arising as a new promising approach for the treatment of neurodegenerative disorders. In particular, mesenchymal stem cells (MSCs) seem the most suitable type of stem cells, thanks to their demonstrated beneficial effects in different experimental models, to the easy availability, and to the lack of ethical problems. In this review, we focused on the studies involving ALS rodent models and clinical trials in order to understand the potential beneficial effects of MSC transplantation. In different ALS rodent models, the administration of MSCs induced a delay in disease progression and at least a partial recovery of the motor function. In addition, clinical trials evidenced the feasibility and safety of MSC transplantation in ALS patients, given that no major adverse events were recorded. However, only partial improvements were shown. For this reason, more studies and trials are needed to clarify the real effectiveness of MSC-based therapy in ALS.
ALS Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
ALSMesenchymal Stromal Cell Therapies for Neurodegenerative Diseases
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson’s disease, and Alzheimer’s disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward side effects.
ALSNurOwn, phase 2, randomized, clinical trial in patients with ALS
A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.
ALSPathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.
Alzheimer’s Alzheimer’s Disease and Stem Cell Therapy
Sung S. Choi, et al.
The loss of neuronal cells in the central nervous system may occur in many neurodegenerative diseases. Alzheimer’s disease is a common senile disease in people over 65 years, and it causes impairment characterized by the decline of mental function, including memory loss and cognitive impairment, and affects the quality of life of patients. However, the current therapeutic strategies against AD are only to relieve symptoms, but not to cure it. Because there are only a few therapeutic strategies against Alzheimer’s disease, we need to understand the pathogenesis of this disease. Cell therapy may be a powerful tool for the treatment of Alzheimer’s disease. This review will discuss the characteristics of Alzheimer’s disease and various available therapeutic strategies.
Alzheimer’s Immunomodulatory role of mesenchymal stem cells in Alzheimer’s disease
Lu Zhang, Zhi-fang Don, Jie-yuanZhang
Alzheimer’s disease (AD) is one of the most common causes of dementia and is characterized by gradual loss in memory, language, and cognitive function. The hallmarks of AD include extracellular amyloid deposition, intracellular neuronal fiber entanglement, and neuronal loss. Despite strenuous efforts toward improvement of AD, there remains a lack of effective treatment and current pharmaceutical therapies only alleviate the symptoms for a short period of time. Interestingly, some progress has been achieved in treatment of AD based on mesenchymal stem cell (MSC) transplantation in recent years. MSC transplantation, as a rising therapy, is used as an intervention in AD, because of the enormous potential of MSCs, including differentiation potency, immunoregulatory function, and no immunological rejection. Although numerous strategies have focused on the use of MSCs to replace apoptotic or degenerating neurons, recent studies have implied that MSC-immunoregulation, which modulates the activity state of microglia or astrocytes and mediates neuroinflammation via several transcription factors (NFs) signaling pathways, may act as a major mechanism for the therapeutic efficacy of MSC and be responsible for some of the satisfactory results. In this review, we will focus on the role of MSC-immunoregulation in MSC-based therapy for AD.
Alzheimer’s Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases
Nathan P. Staff, M.D., Ph.D., David T. Jones, M.D., and Wolfgang Singer, M.D.
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson’s disease, and Alzheimer’s disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward side effects.
Alzheimer’s Regenerative Stem Cell Therapy for Neurodegenerative Diseases: An Overview
Farzane Sivandzade, and Luca Cucullo
Neurodegenerative diseases resulting from the progressive loss of structure and/or function of neurons contribute to different paralysis degrees and loss of cognition and sensation. The lack of successful curative therapies for neurodegenerative disorders leads to a considerable burden on society and a high economic impact. Over the past 20 years, regenerative cell therapy, also known as stem cell therapy, has provided an excellent opportunity to investigate potentially powerful innovative strategies for treating neurodegenerative diseases. This is due to stem cells’ capability to repair injured neuronal tissue by replacing the damaged or lost cells with differentiated cells, providing a conducive environment that is in favor of regeneration, or protecting the existing healthy neurons and glial cells from further damage. Thus, in this review, the various types of stem cells, the current knowledge of stem-cell-based therapies in neurodegenerative diseases, and the recent advances in this field are summarized. Indeed, a better understanding and further studies of stem cell technologies cause progress into realistic and efficacious treatments of neurodegenerative disorders.
Alzheimer’s Stem cell therapies for Alzheimer’s disease is it time?
Wang, Sheng-Mina; Lee, Chang-Ukb; Lim, Hyun Kooka
In terms of mechanism of actions, recent research focused on the interplay between amyloid-beta Aβ (and tau), neurons, and glia. Stem cells can induce direct regeneration of neurons and synapses. They can also prevent activation of pro-inflammatory microglia, promote activation of anti-inflammatory microglia, inhibit astrogliosis, and promote nonreactive astrocytes. These effects in return may increase amyloid-beta (Aβ) degradation, decrease the risk of the Aβ cascade, repair injured neurons, and enhance synaptogenesis. Two completed and nine ongoing clinical trials using diverse stem cells and administration methods (intravenous, subcutaneous, and intra-cranial) were found for the treatment of Alzheimer’s disease. Although stem cell therapy shows great potential to become a prospective treatment for Alzheimer’s disease in the future, these studies are still in their early stages and more studies showing safety and efficacy are needed.
Alzheimer’s Stem cell therapy for Alzheimer’s disease
Xin-Yu Liu, Lin-Po Yang, and Lan Zhao
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell–derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.
Alzheimer’s Stem cell therapy in Alzheimer’s disease: possible benefits and limiting drawbacks
Masoume Alipour, et al.
Alzheimer’s disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients’ pain.
Alzheimer’s Stem Cell Treatment for Alzheimer’s Disease
Ming Li, Kequan Guo, and Susumu Ikehara
Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD.
Alzheimer’s Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer’s Disease
Ankit Tandon, et al.
Alzheimer’s disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
Asthma Mesenchymal Stem Cells Recruit CCR2+ Monocytes to Suppress Allergic Airway Inflammation
Katsuyuki Takeda et al.
Mesenchymal stem cells (MSC) exert immune modulatory properties and previous studies demonstrated suppressive effects of MSC treatment in animal models of allergic airway inflammation. However, the underlying mechanisms have not been fully elucidated. We studied the role of MSC in immune activation and subsequent recruitment of monocytes in suppressing airway hyperresponsiveness and airway inflammation using a mouse model of allergic airway inflammation. MSC administration prior to or after allergen challenge inhibited the development of airway inflammation in allergen-sensitized mice. This was accompanied by an influx of CCR2-positive monocytes, which were localized around injected MSC in the lungs. Notably, IL-10-producing monocytes and/or macrophages were also increased in the lungs. Systemic administration of liposomal clodronate or a CCR2 antagonist significantly prevented the suppressive effects of MSC. Activation of MSC by IFN-γ leading to the upregulation of CCL2 expression was essential for the suppressive effects, as administration of wild-type (WT) MSC into IFN-γ–deficient recipients, or IFN-γ receptor- or CCL2-deficient MSC into WT mice failed to suppress airway inflammation. These results suggest that MSC activation by IFN-γ, followed by increased expression of CCL2 and recruitment of monocytes to the lungs, is essential for suppression by MSC in allergen-induced airway hyperresponsiveness and airway inflammation.
Asthma Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages
Shu-Bin Fang et al.
Allergic airway inflammation is a major public health disease that affects up to 300 million people in the world. However, its management remains largely unsatisfactory. The dysfunction of pulmonary macrophages contributes greatly to the development of allergic airway inflammation. It has been reported that small extracellular vesicles derived from mesenchymal stromal cells (MSC-sEV) were able to display extensive therapeutic effects in some immune diseases. This study aimed to investigate the effects of MSC-sEV on allergic airway inflammation, and the role of macrophages involved in it. We successfully isolated MSC-sEV by using anion exchange chromatography, which were morphologically intact and positive for the specific EV markers. MSC-sEV significantly reduced infiltration of inflammatory cells and number of epithelial goblet cells in lung tissues of mice with allergic airway inflammation. Levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid were also significantly decreased. Importantly, levels of monocytes-derived alveolar macrophages and M2 macrophages were significantly reduced by MSC-sEV. MSC-sEV were excreted through spleen and liver at 24 h post-administration in mice, and were able to be taken in by macrophages both in vivo and in vitro. In addition, proteomics analysis of MSC-sEV revealed that the indicated three types of MSC-sEV contained different quantities of proteins and shared 312 common proteins, which may be involved in the therapeutic effects of MSC-sEV. In total, our study demonstrated that MSC-sEV isolated by anion exchange chromatography were able to ameliorate Th2-dominant allergic airway inflammation through immunoregulation on pulmonary macrophages, suggesting that MSC-sEV were promising alternative therapy for allergic airway inflammation in the future.
Stem Cell Therapy for Autism
Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence
is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or
autism is the most common form of ASD. Although several neurophysiological alterations have
been associated with autism, immune abnormalities and neural hypoperfusion appear to be broadly
consistent. These appear to be causative since correlation of altered inflammatory responses, and
hypoperfusion with symptology is reported. Mesenchymal stem cells (MSC) are in late phases of
clinical development for treatment of graft versus host disease and Crohn’s Disease, two conditions
of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators,
having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral
ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children
receiving cord blood CD34+ cells. We propose the combined use of MSC and cord blood
CD34+cells may be useful in the treatment of autism.
Autoimmune Evaluation of the Therapeutic Potential of Mesenchymal Stem Cells (MSCs) in Preclinical Models of Autoimmune Diseases
Radha Krishan Shandil
Stem cell/MSC transplantation treatment is emerging as a rational and alternative therapeutic option for chronic autoimmune disorders like RA, SLE, and type 1 and type 2 diabetes. Undoubtedly, preclinical models of RA and SLE have played a significant role in deciphering underlying immune mechanisms, pathologies, and evaluation of the therapeutic potential of MSCs.
Autoimmune Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study
Lamei Cheng
Psoriasis is a common, chronic immune-mediated systemic disease that had no effective and durable treatment. Mesenchymal stem cells (MSCs) have immunomodulatory properties. Therefore, we performed a phase 1/2a, single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs (UMSCs) in the treatment of psoriasis and to preliminarily explore the possible mechanisms. Seventeen patients with psoriasis were enrolled and received UMSC infusions. Adverse events, laboratory parameters, PASI, and PGA were analyzed. We did not observe obvious side effects during the treatment and 6-month follow-up. A total of 47.1% (8/17) of the psoriasis patients had at least 40% improvement in the PASI score, and 17.6% (3/17) had no sign of disease or minimal disease based on the PGA score. And the efficiency was 25% (2/8) for males and 66.7% (6/9) for females. After UMSC transplantation (UMSCT), the frequencies of Tregs and CD4+ memory T cells were significantly increased, and the frequencies of T helper (Th) 17 and CD4+ naive T cells were significantly decreased in peripheral blood (PB) of psoriasis patients. And all responders showed significant increases in Tregs and CD4+ memory T cells, and significant decreases in Th17 cells and serum IL-17 level after UMSCT. And baseline level of Tregs in responders were significantly lower than those in nonresponders. In conclusion, allogeneic UMSCT is safe and partially effective in psoriasis patients, and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT.
Autoimmune Immunoregulation by Mesenchymal Stem Cells: Biological Aspects and Clinical Applications
Marta E. Castro-Manrreza and Juan J. Montesinos
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD).
Allogeneic Stem Cells for Autoimmune Disease:
The Preferred Choice
Autoimmune Disease
• Abnormal immune response to a normal body part
*No cure
• Greater than 100 different ones
• 7% of the U.S. population (24 million people)
Abstract
Background: Chronic renal failure is an important clinical problem with significant socioeconomic impact
worldwide. Thoracic spinal cord entrapment induced by a metabolic yield deposit in patients with renal failure
results in intrusion of nervous tissue and consequently loss of motor and sensory function. Human umbilical cord
mesenchymal stem cells are immune naïve and they are able to differentiate into other phenotypes, including the
neural lineage. Over the past decade, advances in the field of regenerative medicine allowed development of cell
therapies suitable for kidney repair. Mesenchymal stem cell studies in animal models of chronic renal failure have
uncovered a unique potential of these cells for improving function and regenerating the damaged kidney
Chronic Inflammation Immune modulation by mesenchymal stem cells
Wei Jiang, et al.
Mesenchymal stem cells (MSCs) can be derived from various adult tissues with multipotent and self‐renewal abilities. The characteristics of presenting no major ethical concerns, having low immunogenicity and possessing immune modulation functions make MSCs promising candidates for stem cell therapies. MSCs could promote inflammation when the immune system is underactivated and restrain inflammation when the immune system is overactivated to avoid self‐overattack. These cells express many immune suppressors to switch them from a pro‐inflammatory phenotype to an anti‐inflammatory phenotype, resulting in immune effector cell suppression and immune suppressor cell activation. We would discuss the mechanisms governing the immune modulation function of these cells in this review, especially the immune‐suppressive effects of MSCs.
Chronic Inflammation Shattering barriers toward clinically meaningful MSC therapies
Oren Levy, et al.
More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.
Introduction
Over the past several decades, there has been increasing interest in perinatal
stem cells for use in the clinic, as a cell-based therapy and as the starting
material for regenerative medicine-based products. In the broader sense,
perinatal stem cells are stem cells derived from the various tissue sources
related to pregnancy. These sources include umbilical cord blood (UCB),
umbilical cord (UC) tissue/Wharton’s Jelly (WJ), amniotic fluid, amnion, placental
tissue, and placental blood. Specifically, perinatal stem cells can refer to stem
cells that are derived from the fetus or mother, depending on the genetic origin of
the after-birth tissue.
Abstract Stem cells hold great promise for treating and, ultimately, curing diseases that are currently being managed with pharmaceutical intervention to control the disease progression and/or disease-related manifestations. Stem cells can be used to regenerate normal cells and tissue, while replacing diseased cells and tissue, in order to restore homeostasis and normal tissue function. Although, there is currently great ethical debate concerning embryonic stem cells— specifically in regards to the dilemma of terminating (potential) life, in order to derive stem cells that could be used to treat and potentially cure another ailing individual—no such ethical quandaries exist with adult stem cell sources—with appropriate patient education and consent. In fact, adult stem cell treatments have been in use for more than 50 years, beginning with the first bone marrow transplants spearheaded in the 1950s to organ transplantations of today. As the stem cell field moves forward towards the next generation of cell-based and regenerative medicine therapies, a new paradigm is being explored as a valuable source of primitive stem cells—otherwise known as perinatal stem cells. This chapter explores, in depth, the potential clinical use and benefit of perinatal stem cells and analogous regenerative medicine therapies sourced from the umbilical cord tissue and Wharton’s Jelly View study
Abstract
Enzymes are commonly used as a biochemical means to liberate cells from a host of tissues for use in in vitro studies and/or in
vivo transplantations. However, very little understanding exists of the biological and functional effects that enzymes have on
cells during the process of releasing the native cells from a given tissue. One specific reason for this is that no technology has
existed as a nonenzymatic control to compare baseline biology and function for a given processed tissue. We have developed a
sterile, onetime use, disposable system (referred to as the AuxoCell Processing System or AC:Px1) that allows for processing of solid tissue in a closed, standardized system using mechanical means to liberate cells without the need and/or use of
any biochemical, enzymatic digestion. In this report, for the first time, we directly compare the cellular outputs derived from
processing the same umbilical cord tissue (UCT) in the presence and absence of collagenase. In the presence of collagenase,
we observed on average, approximately a 2.7-fold reduction in native mesenchymal stem/stromal cell (MSC) yields and a
reduction in MSC-specific markers CD90, CD29, CD105, CD73, CD44, CD36, CD49b, CD49a, CD146, CD295, and CD166
and in endothelial marker CD31. These data directly exhibit that the use of collagenase to process UCT to release cells
impacts cell recovery with respect to number and cell surface marker expression and, hence, could affect the in vivo function
of the recovered native cellular population.
Abstract:
Various source-derived mesenchymal stem cells (MSCs) have been considered
for cell therapeutics in incurable diseases. To characterize MSCs from different sources,
we compared human bone marrow (BM), adipose tissue (AT), and umbilical cord
blood-derived MSCs (UCB-MSCs) for surface antigen expression, differentiation ability,
proliferation capacity, clonality, tolerance for aging, and paracrine activity. Although
MSCs from different tissues have similar levels of surface antigen expression,
immunosuppressive activity, and differentiation ability, UCB-MSCs had the highest rate of
cell proliferation and clonality, and significantly lower expression of p53, p21, and p16,
well known markers of senescence. Since paracrine action is the main action of MSCs, we
examined the anti-inflammatory activity of each MSC under lipopolysaccharide (LPS)-induced
inflammation. Co-culture of UCB-MSCs with LPS-treated rat alveolar macrophage,
reduced expression of inflammatory cytokines including interleukin-1α (IL-1α), IL-6, and
IL-8 via angiopoietin-1 (Ang-1). Using recombinant Ang-1 as potential soluble paracrine
OPEN ACCESS
Int. J. Mol. Sci. 2013, 14 17987
factor or its small interference RNA (siRNA), we found that Ang-1 secretion was responsible
for this beneficial effect in part by preventing inflammation. Our results demonstrate that
primitive UCB-MSCs have biological advantages in comparison to adult sources, making
UCB-MSCs a useful model for clinical applications of cell therapy
COPD Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study
Phuong Le Thi Bich, et al.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD results from chronic inflammation of the lungs. Current treatments, including physical and chemical therapies, provide limited results. Stem cells, particularly mesenchymal stem cells (MSCs), are used to treat COPD. Here, we evaluated the safety and efficacy of umbilical cord-derived (UC)-MSCs for treating COPD.
COPD Can Youthful Mesenchymal Stem Cells from Wharton’s Jelly Bring a Breath of Fresh Air for COPD?
Andrzej M. Janczewski, et al.
Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD.
COPD Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD)
Noridzzaida Ridzuan, et al.
Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin.
COPD Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science
Shih-Lung Cheng, et al.
Patients with chronic obstructive pulmonary disease (COPD) have chronic, irreversible airway inflammation; currently, there is no effective or curative treatment and the main goals of COPD management are to mitigate symptoms and improve patients’ quality of life. Stem cell based therapy offers a promising therapeutic approach that has shown potential in diverse degenerative lung diseases. Preclinical studies have demonstrated encouraging outcomes of mesenchymal stem/stromal cells (MSCs) therapy for lung disorders including emphysema, bronchopulmonary dysplasia, fibrosis, and acute respiratory distress syndrome. This review summarizes available data on 15 studies currently registered by the ClinicalTrials.gov repository, which used different stem cell therapy protocols for COPD; these included bone marrow mononuclear cells (BMMCs), bone marrow-derived MSCs, adipose-derived stem/stromal cells (ADSCs), and adipose-derived MSCs. Published results of three trials indicate that administering BMMCs or MSCs in the setting of degenerative lung disease is safe and may improve patients’ condition and quality of life; however, larger-scale studies are needed to evaluate efficacy. Results of another completed trial (NCT01872624) are not yet published, and eleven other studies are ongoing; these include MSCs therapy in emphysema, several studies of ADSCs in COPD, another in idiopathic pulmonary fibrosis, and plerixafor mobilization of CD117 stem cells to peripheral blood.
COPD Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell
Ajinkya C Inamdar, et al.
Lung disorders such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive lung disease (COPD), and interstitial lung disease (ILD) show a few common threads of pathogenic mechanisms: inflammation, aberrant immune activity, infection, and fibrosis. Currently no modes of effective treatment are available for ILD or emphysema. Being anti-inflammatory, immunomodulatory, and regenerative in nature, the administration of mesenchymal stem cells (MSCs) has shown the capacity to control immune dysfunction and inflammation in the lung. The intravenous infusion of MSCs, the common mode of delivery, is followed by their entrapment in lung vasculature before MSCs reach to other organ systems thus indicating the feasible and promising approach of MSCs therapy for lung diseases. In this review, we discuss the mechanistic basis for MSCs therapy for asthma, ARDS, COPD, and ILD.
COPD Mesenchymal stem cells and immunomodulation: current status and future prospects
F Gao, et al.
The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.
COPD Mesenchymal stromal cell therapy in COPD: from bench to bedside
Mariana A Antunes, et al.
COPD is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality. The major risk factor for COPD development is cigarette smoke, and the most efficient treatment for COPD is smoking cessation. However, even after smoking cessation, inflammation, apoptosis, and oxidative stress may persist and continue contributing to disease progression. Although current therapies for COPD (primarily based on anti-inflammatory agents) contribute to the reduction of airway obstruction and minimize COPD exacerbations, none can avoid disease progression or reduce mortality. Within this context, recent advances in mesenchymal stromal cell (MSC) therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. MSCs can be readily harvested from diverse tissues and expanded with high efficiency, and have strong immunosuppressive properties. Preclinical studies have demonstrated encouraging outcomes of MSCs therapy for lung disorders, including emphysema. These findings instigated research groups to assess the impact of MSCs in human COPD/emphysema, but clinical results have fallen short of expectations. However, MSCs have demonstrated a good adjuvant role in the clinical scenario. Trials that used MSCs combined with another, primary treatment (eg, endobronchial valves) found that patients derived greater benefit in pulmonary function tests and/or quality of life reports, as well as reductions in systemic markers of inflammation. The present review summarizes and describes the more recent preclinical studies that have been published about MSC therapy for COPD/emphysema and discusses what has already been applied about MSCs treatment in COPD patients in the clinical setting.
COPD Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases
Massimo Conese, et al.
Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders.
COPD Preclinical Studies of Mesenchymal Stem Cell (MSC) Administration in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis
Xiangde Liu, et al.
In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD). The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models.
COPD Stem cell therapy in chronic obstructive pulmonary disease. How far is it to the clinic?
Nurdan Kokturk, et al.
Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. However, in the latter stages of the disease, the airways become largely obstructed and lung parenchyma becomes destructed due to underlying inflammation. The inappropriate repair of lung tissue after injury may contribute to the development of disease. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. Endogenous and exogenous sources of stem cells are available for the treatment of many diseases. Stem cell therapy is newly introduced to the field of COPD. Currently the research is in its infancy; however, the field is profoundly growing. Previous studies suggest that cell-based therapies and novel bioengineering approaches may be potential therapeutic strategies for lung repair and remodelling. In this paper, we review the current evidence of stem cell therapy in COPD.
Preclinical Studies of Mesenchymal Stem Cell
(MSC) Administration in Chronic Obstructive
Pulmonary Disease (COPD): A Systematic
Abstract
Background
In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in
the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD). The aim of the current study was to systematically review and conduct a
meta-analysis on the published pre-clinical studies of MSC administration in the treatment
of COPD in animal models.
Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. We summarized the progress made by regenerative therapies for COPD by analyzing results from both pre-clinical studies and completed clinical trials. These approaches include the application of exogenous stem cells or small molecules to stimulate the regeneration by endogenous lung stem/progenitor cells. Exogenous mesenchymal stem cells (MSCs) have been reported to repair the structure and improve the function of the injured respiratory system in COPD models. However, the studies that used MSCs in patients with moderate-to-severe COPD patients did not lead to clear respiratory functional improvements. Exogenous human lung stem cells applied to cryo-injured (CI) lungs of mice have been shown to organize into human-like pulmonary structures, indicating a new property of stem cells that is potentially capable of curing COPD patients. Small molecules like retinoic acid has been shown to lead to regeneration and repair of the damaged lung structures in COPD mouse models probably by activation of endogenous lung stem/progenitor cells. However, retinoic acid or agonists of retinoic acid receptor administered to moderate or severe COPD patients did not improve the density and function of the damaged lung. These novel regenerative approaches have failed in preliminary clinical trials, possibly due to the advanced severity of the disease. Further work should be done to develop the current regenerative approaches for curing patients at different stages of COPD. We suggest that some modifications of the approach in the clinical studies may lead to more successful outcomes of regenerative therapy for COPD.
COVID-19 Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment
Hamid Reza Aghayan
Our results demonstrated that intravenous administration of PL-MSCs in patients with COVID-19 related ARDS is safe and feasible. Further studies whit higher cell doses and repeated injections are needed to evaluate the efficacy of this treatment modality.
COVID-19 Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series
Seyed-Mohammad Reza Hashemian et al.
We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.
COVID-19 Promising role for mesenchymal stromal cells in coronavirus infectious disease-19 (COVID-19)-related severe acute respiratory syndrome?
Hamdan Hamdan et al.
Mesenchymal stromal cells (MSC) have immune regulatory and tissue regenerative properties. MSCs are being studied as a therapy option for many inflammatory and immune disorders and are approved to treat acute graft-versus-host disease (GvHD). The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic and associated coronavirus infectious disease-19 (COVID-19) has claimed many lives. Innovative therapies are needed. Preliminary data using MSCs in the setting of acute respiratory distress syndrome (ARDS) in COVID-19 are emerging. We review mechanisms of action of MSCs in inflammatory and immune conditions and discuss a potential role in persons with COVID-19.
COVID-19 Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients
Christopher J. Rogers et al.
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC’s impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.
COVID-19 Taming of Covid-19: potential and emerging application of mesenchymal stem cells
Nima Najafi-Ghalehlou et al.
Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has turned out to cause a pandemic, with a sky scraping mortality. The virus is thought to cause tissue injury by affecting the renin-angiotensin system. Also, the role of the over-activated immune system is noteworthy, leading to severe tissue injury via the cytokine storms. Thus it would be feasible to modulate the immune system response in order to attenuate the disease severity, as well as treating the patients. Today different medicines are being administered to the patients, but regardless of the efficacy of these treatments, adverse effects are pretty probable. Meanwhile, mesenchymal stem cells (MSCs) prove to be an effective candidate for treating the patients suffering from COVID-19 pneumonia, owing to their immunomodulatory and tissue-regenerative potentials. So far, several experiments have been conducted; transplanting MSCs and results are satisfying with no adverse effects being reported. This paper aims to review the recent findings regarding the novel coronavirus and the conducted experiments to treat patients suffering from COVID-19 pneumonia utilizing MSCs.
COVID-19 Therapeutic implications of mesenchymal stem cells in acute lung injury/acute respiratory distress syndrome
Yan-Yang Wang et al.
Acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. Current treatment of ALI/ARDS is primarily supportive, with lung protective ventilation and fluid conserving strategies. Despite improvement in these strategies, recent data indicate that the mortality of ALI/ARDS is still as high as 30 to 50%. Thus, there is a need for innovative therapies to further improve clinical outcomes of ALI/ARDS. Recent studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI/ARDS have shown promising results. This review focuses on existing studies that have tested the use of MSCs in models of ALI/ARDS, and the potential mechanisms underlying their therapeutic effects.
Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.
Crohn’s Disease Efficacy of stem cells therapy for Crohn’s fistula: a meta-analysis and systematic review
Yantian Cao, et al.
Fistulas have puzzled us all the time and stem cell therapy for it is still in its infancy. We conducted a meta-analysis and systematic review to evaluate the efficacy of stem cells and its potential mechanisms in the management of Crohn’s fistula.
Crohn’s Disease Ex vivo immunosuppressive effects of mesenchymal stem cells on Crohn’s disease mucosal T cells are largely dependent on indoleamine 2,3-dioxygenase activity and cell-cell contact
Rachele Ciccocioppo, et al.
Crohn’s disease (CD) is a disabling chronic enteropathy sustained by a harmful T-cell response toward antigens of the gut microbiota in genetically susceptible subjects. Growing evidence highlights the safety and possible efficacy of mesenchymal stem cells (MSCs) as a new therapeutic tool for this condition. Therefore, we aimed to investigate the effects of bone marrow-derived MSCs on pathogenic T cells with a view to clinical application.
Crohn’s Disease Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial
Prof Julián Panés MD, et al.
Complex perianal fistulas in Crohn’s disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn’s disease.
Crohn’s Disease Mesenchymal Stem Cells for Perianal Crohn’s Disease
Michele Carvello, et al.
Perianal fistulizing Crohn’s disease (PFCD) is associated with significant morbidity and might negatively impact the quality of life of CD patients. In the last two decades, the management of PFCD has evolved in terms of the multidisciplinary approach involving gastroenterologists and colorectal surgeons. However, the highest fistula healing rates, even combining surgical and anti-TNF agents, reaches 50% of treated patients. More recently, the administration of mesenchymal stem cells (MSCs) have shown notable promising results in the treatment of PFCD. The aim of this review is to describe the rationale and the possible mechanism of action of MSC application for PFCD and the most recent results of randomized clinical trials. Furthermore, the unmet needs of the current administration process and the expected next steps to improve the outcomes will be addressed.
Crohn’s Disease Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders
Alexander Markov, et al.
Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn’s disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.
Crohn’s Disease Mesenchymal stromal cells: clinical challenges and therapeutic opportunities
Jacques Galipeau, and Luc Sensébé
Mesenchymal Stromal Cells (MSCs) have been the subject of clinical trials for more than a generation and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analysis of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.
Crohn’s Disease Umbilical Cord Mesenchymal Stem Cell Treatment for Crohn’s Disease: A Randomized Controlled Clinical Trial
Jian Zhang, et al.
tem cell therapy has been applied to treat a variety of autoimmune diseases, including Crohn’s disease (CD), but few studies have examined the use of umbilical cord mesenchymal stem cells (UC-MSCs). This trial sought to investigate the efficacy and safety of UC-MSCs for the treatment of CD.
Clinical safety in using unmatched allogeneic
umbilical cord blood mononuclear cells
transplantations in nonhaematopoietic
degenerative conditions.
Abstract
AIM: Evaluation of safety in using unmatched human allogeneic
umbilical cord blood cells for therapeutic use in individuals with
nonhaematopoietic degenerative conditions.
Diabetes Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes
Yicheng Qi, Jing Ma, Shengxian Li, and Wei Liu
Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) and impaired insulin secretion. The chronic inflammatory process contributed to IR and could also hamper pancreatic β cell function. However, currently applied treatment cannot reverse β cell damage or alleviate inflammation. Mesenchymal stem cells (MSCs), the cell-based therapy for their self-renewable, differentiation potential, and immunosuppressive properties, have been demonstrated in displaying therapeutic effects in T2DM. Adipose-derived MSCs (AD-MSCs) attracted more attention due to less harvested inconvenience and ethical issues commonly accompany with bone marrow-derived MSCs (BM-MSCs) and fetal annex-derived MSCs. Both AD-MSC therapy studies and mechanism explorations in T2DM animals presented that AD-MSCs could translate to clinical application. However, hyperglycemia, hyperinsulinemia, and metabolic disturbance in T2DM are crucial for impairment of AD-MSC function, which may limit the therapeutical effects of MSCs. This review focuses on the outcomes and the molecular mechanisms of MSC therapies in T2DM which light up the hope of AD-MSCs as an innovative strategy to cure T2DM.
Diabetes Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data
Jingjing He et al.
Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs).
Diabetes Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes
Wei Zhang
Both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications.
Diabetes Current Status of Stem Cell Treatment for Type I Diabetes Mellitus
Anupama Kakkar, et al.
Diabetes mellitus is a major health concern in current scenario which has been found to affect people of almost all ages. The disease has huge impact on global health; therefore, alternate methods apart from insulin injection are being explored to cure diabetes. Therefore, this review mainly focuses on the current status and therapeutic potential of stem cells mainly mesenchymal stem cells (MSCs) for Type 1 diabetes mellitus in preclinical animal models as well as humans.
Diabetes Identifying the Therapeutic Significance of Mesenchymal Stem Cells
Vineet Kumar Mishra, et al.
The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.
Diabetes Immunomodulation by Mesenchymal Stem Cells
Reza Abdi, et al.
Mesenchymal stem cells (MSCs) are pluripotent stromal cells that have the potential to give rise to cells of diverse lineages. Interestingly, MSCs can be found in virtually all postnatal tissues. The main criteria currently used to characterize and identify these cells are the capacity for self-renewal and differentiation into tissues of mesodermal origin, combined with a lack in expression of certain hematopoietic molecules. Because of their developmental plasticity, the notion of MSC-based therapeutic intervention has become an emerging strategy for the replacement of injured tissues. MSCs have also been noted to possess the ability to impart profound immunomodulatory effects in vivo. Indeed, some of the initial observations regarding MSC protection from tissue injury once thought mediated by tissue regeneration may, in reality, result from immunomodulation. Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown, these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. This article focuses on recent advances that have broadened our understanding of the immunomodulatory properties of MSC and provides insight as to their potential for clinical use as a cell-based therapy for immune-mediated disorders and, in particular, type 1 diabetes.
Diabetes Mesenchymal Stem Cells as New Therapeutic Approach for Diabetes and Pancreatic Disorders
Arianna Scuteri and Marianna Monfrini
Diabetes is a worldwide disease which actually includes different disorders related to glucose metabolism. According to different epidemiological studies, patients affected by diabetes present a higher risk to develop both acute and chronic pancreatitis, clinical situations which, in turn, increase the risk to develop pancreatic cancer. Current therapies are able to adjust insulin levels according to blood glucose peak, but they only partly reach the goal to abrogate the consequent inflammatory milieu responsible for diabetes-related diseases. In recent years, many studies have investigated the possible use of adult mesenchymal stem cells (MSCs) as alternative therapeutic treatment for diabetes, with promising results due to the manifold properties of these cells. In this review we will critically analyze the many different uses of MSCs for both diabetes treatment and for the reduction of diabetes-related disease development, focusing on their putative molecular mechanisms.
Diabetes Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes
L.Vijaab, et al.
Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic β cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.
Diabetes Regenerative and Transplantation Medicine: Cellular Therapy Using Adipose Tissue-Derived Mesenchymal Stromal Cells for Type 1 Diabetes Mellitus
Hiroyuki Takahashi et al.
Type 1 diabetes mellitus (T1DM) is caused by the autoimmune targeting of pancreatic β-cells, and, in the advanced stage, severe hypoinsulinemia due to islet destruction. In patients with T1DM, continuous exogenous insulin therapy cannot be avoided. However, an insufficient dose of insulin easily induces extreme hyperglycemia or diabetic ketoacidosis, and intensive insulin therapy may cause hypoglycemic symptoms including hypoglycemic shock. While these insulin therapies are efficacious in most patients, some additional therapies are warranted to support the control of blood glucose levels and reduce the risk of hypoglycemia in patients who respond poorly despite receiving appropriate treatment. There has been a recent gain in the popularity of cellular therapies using mesenchymal stromal cells (MSCs) in various clinical fields, owing to their multipotentiality, capacity for self-renewal, and regenerative and immunomodulatory potential. In particular, adipose tissue-derived MSCs (ADMSCs) have become a focus in the clinical setting due to the abundance and easy isolation of these cells. In this review, we outline the possible therapeutic benefits of ADMSC for the treatment of T1DM.
Diabetes Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells
Nadine E. Rekittke et al.
Type 1 diabetes is an autoimmune disease resulting in the permanent destruction of pancreatic islets. Islet transplantation to portal vein provides an approach to compensate for loss of insulin producing cells. Clinical trials demonstrated that even partial islet graft function reduces severe hypoglycemic events in patients. However, therapeutic impact is restrained due to shortage of pancreas organ donors and instant inflammation occurring in the hepatic environment of the graft. We summarize on what is known about regenerative therapy in type 1 diabetes focusing on pancreatic islet transplantation and new avenues of cell substitution. Metabolic pathways and energy production of transplanted cells are required to be balanced and protection from inflammation in their intravascular bed is desired. Mesenchymal stem cells (MSCs) have anti-inflammatory features, and so they are interesting as a therapy for type 1 diabetes. Recently, they were reported to reduce hyperglycemia in diabetic rodents, and they were even discussed as being turned into endodermal or pancreatic progenitor cells. MSCs are recognized to meet the demand of an individual therapy not raising the concerns of embryonic or induced pluripotent stem cells for therapy.
Diabetes Stem cells as a potential therapy for diabetes mellitus: a call-to-action in Latin America
Mairim Alexandra Solis, et al.
Latin America is a fast-growing region that currently faces unique challenges in the treatment of all forms of diabetes mellitus. The burden of this disease will be even greater in the coming years due, in part, to the large proportion of young adults living in urban areas and engaging in unhealthy lifestyles. Unfortunately, the national health systems in Latin-American countries are unprepared and urgently need to reorganize their health care services to achieve diabetic therapeutic goals. Stem cell research is attracting increasing attention as a promising and fast-growing field in Latin America. As future healthcare systems will include the development of regenerative medicine through stem cell research, Latin America is urged to issue a call-to-action on stem cell research. Increased efforts are required in studies focused on stem cells for the treatment of diabetes. In this review, we aim to inform physicians, researchers, patients and funding sources about the advances in stem cell research for possible future applications in diabetes mellitus. Emerging studies are demonstrating the potential of stem cells for β cell differentiation and pancreatic regeneration. The major economic burden implicated in patients with diabetes complications suggests that stem cell research may relieve diabetic complications. Closer attention should be paid to stem cell research in the future as an alternative treatment for diabetes mellitus.
Diabetes Therapeutic Potential of Mesenchymal Stem Cells for Diabetes
Alvaro Moreira, et al.
Mesenchymal stem cells (MSCs) are self-renewing multipotent cells that have the capacity to secrete multiple biologic factors that can restore and repair injured tissues. Preclinical and clinical evidence have substantiated the therapeutic benefit of MSCs in various medical conditions. Currently, MSCs are the most commonly used cell-based therapy in clinical trials because of their regenerative effects, ease of isolation, and low immunogenicity. Experimental and clinical studies have provided promising results using MSCs to treat diabetes. This review will summarize the role of MSCs on tissue repair, provide emerging strategies to improve MSC function, and describe how these processes translate to clinical treatments for diabetes.
Diabetes Therapeutic Potential of Wharton’s Jelly Mesenchymal Stem Cells for Diabetes: Achievements and Challenges
Mohamed M. Kamal, et al.
Diabetes mellitus (DM) is an alarming metabolic disease in which insulin secreting β-cells are damaged to various extent. Unfortunately, although currently available treatments help to manage the disease, however, patients usually develop complications, as well as decreased life quality and increased mortality. Thus, efficient therapeutic interventions to treat diabetes are urgently warranted. During the past years, mesenchymal stem cells (MSCs) have made their mark as a potential weapon in various regenerative medicine applications. The main fascination about MSCs lies in their potential to exert reparative effects on an amazingly wide spectrum of tissue injury. This is further reinforced by their ease of isolation and large ex vivo expansion capacity, as well as demonstrated multipotency and immunomodulatory activities. Among all the sources of MSCs, those isolated from umbilical cord-Wharton’s jelly (WJ-MSCs), have been proved to provide a great source of MSCs. WJ-MSCs do not impose any ethical concerns as those which exist regarding ESCs, and represent a readily available non-invasive source, and hence suggested to become the new gold standard for MSC-based therapies. In the current review, we shall overview achievements, as well as challenges/hurdles which are standing in the way to utilize WJ-MSCs as a novel efficient therapeutic modality for DM.
A preliminary evaluation of efficacy and safety
of Wharton’s jelly mesenchymal stem cell
transplantation in patients with type 2 diabetes
mellitus
Abstract
Introduction: Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus
(T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton’s Jelly-derived mesenchymal
stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective
phase I/II study to determine efficacy and safety of WJ-MSC transplantation in T2DM.
Abstract
Background: Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes
(T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses
by altering regulatory T cells (Tregs) and human islet b cell-specific T cell clones offers promise for a new approach
to overcome the autoimmunity underlying T1D.
Treatment of Diabetic Impotence with Umbilical Cord Blood
Stem Cell Intracavernosal Transplant:
Abstract
Objectives: Stem cells are characterized by self
renewal and multipotent differentiation. We report
the effects of intracavernosal transplant of human
umbilical cord blood stem cells on diabetic erectile
dysfunction.
Materials and Methods: Seven type 2 diabetics who
had failed to achieve an erection for at least 6
months despite medications, and who are currently
awaiting penile prostheses, participated. All
laboratory results were normal, except for
impotence and diabetes mellitus. A total of
1.5 × 107 human umbilical cord blood stem cells
were infused into the corpus cavernosum. No
immunosuppressive measures were taken in any of
the patients. International index of erectile
function-5, SEP, GAQ, erection diary, blood glucose
diary, and medication dosage were followed for 9
months.
View study
Tissue-specifc Diferentiation
Potency of Mesenchymal Stromal
Cells from Perinatal Tissues
Human perinatal tissue is an abundant source of mesenchymal stromal cells(MSCs) and lacks the
ethical concerns. Perinatal MSCs can be obtained from various tissues as like amnion, chorion, and
umbilical cord. Still, little is known of the distinct nature of each MSC type. In this study, we successfully
isolated and cultured MSCs from amnion(AMSCs), chorion(CMSCs), and umbilical cord(UC-MSCs).
Proliferation potential was diferent among them, that AMSCs revealed the lowest proliferation rate
due to increased Annexin V and senescence-associated β-galactosidase positive cells. We demonstrated
distinct characteristic gene expression according to the source of the original tissue using microarray.
In particular, genes associated with apoptosis and senescence including CDKN2A were up-regulated
in AMSCs. In CMSCs, genes associated with heart morphogenesis and blood circulation including
HTR2B were up-regulated. Genes associated with neurological system processes including NPY were
up-regulated in UC-MSCs. Quantitative RT-PCR confrmed the gene expression data. And in vitro
diferentiation of MSCs demonstrated that CMSCs and UC-MSCs had a more pronounced ability to
diferentiate into cardiomyocyte and neural cells, respectively. This study frstly demonstrated the
innate tissue-specifc diferentiation potency of perinatal MSCs which can be helpful in choosing more
adequate cell sources for better outcome in a specifc disease.
Fibromyalgia Application of Adult and Pluripotent Stem Cells in Interstitial Cystitis/Bladder Pain Syndrome Therapy: Methods and Perspectives
Ahmed Abdal Dayem et al.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic disease without definite etiology characterized by bladder-related pelvic pain. IC/BPS is associated with pain that negatively affects the quality of life. There are various therapeutic approaches against IC/BPS. However, no efficient therapeutic agent against IC/BPS has been discovered yet. Urothelium dysfunction is one of the key factors of IC/BPS-related pathogenicity. Stem cells, including adult stem cells (ASCs) and pluripotent stem cells (PSCs), such as embryonic stem cells (ESCs) and induced PSCs (iPSCs), possess the abilities of self-renewal, proliferation, and differentiation into various cell types, including urothelial and other bladder cells. Therefore, stem cells are considered robust candidates for bladder regeneration. This review provides a brief overview of the etiology, pathophysiology, diagnosis, and treatment of IC/BPS as well as a summary of ASCs and PSCs. The potential of ASCs and PSCs in bladder regeneration via differentiation into bladder cells or direct transplantation into the bladder and the possible applications in IC/BPS therapy are described in detail. A better understanding of current studies on stem cells and bladder regeneration will allow further improvement in the approaches of stem cell applications for highly efficient IC/BPS therapy.
Heart Failure Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity
Henry C. Quevedo et al.
The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (n = 4) or male allogeneic MSCs (200 million; n = 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Ypos) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and α-sarcomeric actin. In addition, Ypos MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 ± 1.7% to 13.9 ± 2.0% (P < 0.001), and ejection fraction (EF) increased from 35.0 ± 1.7% to 41.3 ± 2.7% (P < 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (R = 0.85, P < 0.05) and MBF (R = 0.76, P < 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium.
Heart Failure Mesenchymal Stem Cells in Cardiology
Ian A. White et al.
Cardiovascular disease (CVD) accounts for more deaths globally than any other single disease. There are on average 1.5 million episodes of myocardial infarction (heart attack) each year in the United States alone with roughly one third resulting in death. There is therefore a major need for developing new and effective strategies to promote cardiac repair. Intramyocardial transplantation of mesenchymal stem cells (MSCs) has emerged as a leading contender in the pursuit of clinical intervention and therapy. MSCs are potent mediators of cardiac repair and are therefore an attractive tool in the development of pre-clinical and clinical trials. MSCs are capable of secreting a large array of soluble factors, which have had demonstrated effects on pathogenic cardiac remolding, fibrosis, immune activation and cardiac stem cell proliferation within the damaged heart. MSCs are also capable of differentiation into cardiomyocytes, endothelial cells and vascular smooth muscle cells, although the relative contribution of trilineage differentiation and paracrine effectors on cardiac repair remains the subject of active investigation.
Heart Failure Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue
Samuel Golpanian, et al.
Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs’ effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.
Heart Failure Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue
Samuel Golpanian, Ariel Wolf, Konstantinos E. Hatzistergos, and Joshua M. Hare
Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs’ effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.
Heart Failure Transplantation of mesenchymal stem cells for prevention of acute myocardial infarction induced heart failure: study protocol of a phase III randomized clinical trial (Prevent-TAHA8)
Armin Attar
Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.
Human Umbilical Cord Blood for Transplantation Therapy in
Myocardial Infarction
Cell-based therapy is a promising therapy for myocardial infarction. Endogenous repair of the
heart muscle after myocardial infarction is a challenge because adult cardiomyocytes have a
limited capacity to proliferate and replace damaged cells. Pre-clinical and clinical evidence has
shown that cell based therapy may promote revascularization and replacement of damaged
myocytes after myocardial infarction. Adult stem cells can be harvested from different sources
including bone marrow, skeletal myoblast, and human umbilical cord blood cells. The use of these
cells for the repair of myocardial infarction presents various advantages over other sources of stem
cells. Among these are easy harvesting, unlimited differentiation capability, and robust angiogenic
potential. In this review, we discuss the milestone findings and the most recent evidence
demonstrating the therapeutic efficacy and safety of the transplantation of human umbilical cord
blood cells as a stand-alone therapy or in combination with gene therapy, highlighting the
importance of optimizing the timing, dose and delivery methods, and a better understanding of the
mechanisms of action that will guide the clinical entry of this innovative treatment for ischemic
disorders, specifically myocardial infarction.
Abstract
article-meta
Stem cell transplantation can promote functional restoration following
acute spinal cord injury (injury time 6
months) were treated with human umbilical cord blood stem cells via
intravenous and intrathecal injection. The follow-up period was 12
months after transplantation. Results found that autonomic nerve
functions were restored and the latent period of somatosensory evoked
potentials was reduced. There were no severe adverse reactions in
patients following stem cell transplantation. These experimental findings
suggest that the transplantation of human umbilical cord blood stem
cells is a safe and effective treatment for patients with traumatic spinal
cord injury.
Immunomodulation Human mesenchymal stem cells modulate allogeneic immune cell responses
Sudeepta Aggarwal, Mark F. Pittenger
Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [TH1] and TH2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor α (TNF-α) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused TH1 cells to decrease interferon γ (IFN-γ) and caused the TH2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (TRegs) present; and hMSCs decreased secretion of IFN-γ from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE2) in co-cultures, and inhibitors of PGE2 production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation. (Blood. 2005;105:1815-1822)
Immunomodulation Mesenchymal stem cells and immunomodulation: current status and future prospects
F Gao et al.
The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.
Stem cell-based therapies in inflammatory
bowel disease: promises and pitfalls
Natalie E. Duran and Daniel W. Hommes
Abstract:
Inflammatory bowel disease (IBD) is a chronic, often relapsing, condition that deeply
impacts the quality of life for many patients. Although there have been significant advances in
medical treatments, a large proportion of patients become refractory to available therapeutic
options. Stem-cell therapy through hematopoietic stem cells (HSCs) or mesenchymal
stem (stromal) cells (MSCs) is a promising therapeutic option for severe refractory cases
especially when surgery is not feasible. In HSC transplantation, the objective is to destroy
the ‘autoreactive’ immune cells responsible for disease chronicity, and to re-establish gut
tolerance to gut microbes. In perianal Crohn’s disease (CD), the objective is to deposit MSCs
locally in fistulizing tracts to down-regulate the local immune response and induce wound
healing. Results from upcoming and ongoing clinical trials will set the path of these novel
therapeutic options that have the capability to successfully treat severe refractory Crohn’s
patients.
Abstract:
Over the past few years, substantial progress
has been made in the field of stem cell regeneration of
the intervertebral disc. Autogenic mesenchymal stem
cells in animal models can arrest intervertebral disc
degeneration or even partially regenerate it and the
effect is suggested to be dependent on the severity of
degeneration. Mesenchymal stem cells (MSCs) are
able to escape alloantigen recognition which is an
advantage for allogenic transplantation. A number of
injectable scaffolds have been described and various
methods to pre-modulate MSCs’ activity have been
tested. In future, work will need to address the use of
mesenchymal stem cells in large animal models and
the fate of the implanted mesenchymal stem cells,
particularly in the long term, in animals. This review
examines the state-of-the-art in the field of stem cell
regeneration of the intervertebral disc, and critically
discusses, with scientific support, the issues involved,
before stem cells could be used in human subjects.
Abstract:
Objective: Numerous investigations suggest that Mesenchymal Stem Cells (MSCs) in general represent a
valuable tool for therapy of symptoms related to chronic infammatory diseases. Blue Horizon Stem Cell Therapy
Program is a leading provider of adult and children’s stem cell therapies. Uniquely we have safely and effciently
treated over 600 patients with documenting each procedure.
Long term effects of the implantation of Wharton’s jelly-derived
mesenchymal stem cells from the umbilical cord for newly-onset
type 1 diabetes mellitus
Abstract. T1DM is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to
regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem.
Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term
effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for
Newly-onset Type 1 Diabetes Mellitus (T1DM). Twenty-nine patients with newly onset T1DM were randomly divided into
two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based
on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the frst 3 months and
thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations
were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c
and C peptide in group I patients were signifcantly better than either pretherapy values or group II patients during the
follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe
and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are
unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes
Kidney Disease Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells
Christian Sávio-Silva
Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.
Kidney Disease Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases
Yuling Huang, et al.
Kidney diseases pose a threat to human health due to their rising incidence and fatality rate. In preclinical and clinical studies, it has been acknowledged that mesenchymal stem cells (MSCs) are effective and safe when used to treat kidney diseases. MSCs play their role mainly by secreting trophic factors and delivering extracellular vesicles (EVs). The genetic materials and proteins contained in the MSC-derived EVs (MSC-EVs), as an important means of cellular communication, have become a research focus for targeted therapy of kidney diseases. At present, MSC-EVs have shown evident therapeutic effects on acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and atherosclerotic renovascular disease (ARVD); however, their roles in the transplanted kidney remain controversial. This review summarises the mechanisms by which MSC-EVs treat these diseases in animal models and proposes certain problems, expecting to facilitate corresponding future clinical practice.
Kidney Disease Potential and Therapeutic Efficacy of Cell-based Therapy Using Mesenchymal Stem Cells for Acute/chronic Kidney Disease
Chul Won Yun et al.
Kidney disease can be either acute kidney injury (AKI) or chronic kidney disease (CKD) and it can lead to the development of functional organ failure. Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have immunomodulatory effects to assist in the recovery from tissue injury and the inhibition of inflammation. Numerous studies have investigated the feasibility, safety, and efficacy of MSC-based therapies for kidney disease. Although the exact mechanism of MSC-based therapy remains uncertain, their therapeutic value in the treatment of a diverse range of kidney diseases has been studied in clinical trials. The use of MSCs is a promising therapeutic strategy for both acute and chronic kidney disease. The mechanism underlying the effects of MSCs on survival rate after transplantation and functional repair of damaged tissue is still ambiguous. The paracrine effects of MSCs on renal recovery, optimization of the microenvironment for cell survival, and control of inflammatory responses are thought to be related to their interaction with the damaged kidney environment. This review discusses recent experimental and clinical findings related to kidney disease, with a focus on the role of MSCs in kidney disease recovery, differentiation, and microenvironment. The therapeutic efficacy and current applications of MSC-based kidney disease therapies are also discussed.
Kidney Disease Safety and tolerability of autologous bone marrow mesenchymal stromal cells in ADPKD patients
Atieh Makhlough
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually develop end-stage renal disease (ESRD). We hypothesize that bone marrow mesenchymal stromal cells (BMMSCs) are renotropic and may improve kidney function via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. In this study, we aim to assess the safety and tolerability of a BMMSC infusion in ADPKD patients.
Kidney Disease Stem cell-based treatment of kidney diseases
Binbin Pan et al.
Kidney dysfunction, including chronic kidney disease and acute kidney injury, is a globally prevalent health problem. However, treatment regimens are still lacking, especially for conditions involving kidney fibrosis. Stem cells hold great promise in the treatment of chronic kidney disease and acute kidney injury, but success has been hampered by insufficient incorporation of the stem cells in the injured kidney. Thus, new approaches for the restoration of kidney function after acute or chronic injury have been explored. Recently, kidney organoids have emerged as a useful tool in the treatment of kidney diseases. In this review, we discuss the mechanisms and approaches of cell therapy in acute kidney injury and chronic kidney disease, including diabetic kidney disease and lupus nephritis. We also summarize the potential applications of kidney organoids in the treatment of kidney diseases.
Kidney Disease Stem cells: a potential treatment option for kidney diseases
Dongwei Liu et al.
The prevalence of kidney diseases is emerging as a public health problem. Stem cells (SCs), currently considered as a promising tool for therapeutic application, have aroused considerable interest and expectations. With self-renewal capabilities and great potential for proliferation and differentiation, stem cell therapy opens new avenues for the development of renal function and structural repair in kidney diseases. Mounting evidence suggests that stem cells exert a therapeutic effect mainly by replacing damaged tissues and paracrine pathways. The benefits of various types of SCs in acute kidney disease and chronic kidney disease have been demonstrated in preclinical studies, and preliminary results of clinical trials present its safety and tolerability. This review will focus on the stem cell-based therapy approaches for the treatment of kidney diseases, including various cell sources used, possible mechanisms involved, and outcomes that are generated so far, along with prospects and challenges in clinical application.
Kidney Disease Stem/progenitor cell in kidney: characteristics, homing, coordination, and maintenance
Jiewu Huang et al.
Renal failure has a high prevalence and is becoming a public health problem worldwide. However, the renal replacement therapies such as dialysis are not yet satisfactory for its multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidney and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidney in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis, and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.
Kidney Disease Stem/Stromal Cells for Treatment of Kidney Injuries With Focus on Preclinical Models
Adriana Torres Crigna et al.
Within the last years, the use of stem cells (embryonic, induced pluripotent stem cells, or hematopoietic stem cells), Progenitor cells (e.g., endothelial progenitor cells), and most intensely mesenchymal stromal cells (MSC) has emerged as a promising cell-based therapy for several diseases including nephropathy. For patients with end-stage renal disease (ESRD), dialysis or finally organ transplantation are the only therapeutic modalities available. Since ESRD is associated with a high healthcare expenditure, MSC therapy represents an innovative approach. In a variety of preclinical and clinical studies, MSC have shown to exert renoprotective properties, mediated mainly by paracrine effects, immunomodulation, regulation of inflammation, secretion of several trophic factors, and possibly differentiation to renal precursors. However, studies are highly diverse; thus, knowledge is still limited regarding the exact mode of action, source of MSC in comparison to other stem cell types, administration route and dose, tracking of cells and documentation of therapeutic efficacy by new imaging techniques and tissue visualization. The aim of this review is to provide a summary of published studies of stem cell therapy in acute and chronic kidney injury, diabetic nephropathy, polycystic kidney disease, and kidney transplantation. Preclinical studies with allogeneic or xenogeneic cell therapy were first addressed, followed by a summary of clinical trials carried out with autologous or allogeneic hMSC. Studies were analyzed with respect to source of cell type, mechanism of action etc.
Kidney Disease The therapeutic potential of Camel Wharton jelly mesenchymal stem cells (CWJ-MSCs) in canine chronic kidney disease model
Hala M. F. El Miniawy
The serum urea and creatinine in the treated group were significantly decreased transferring dogs in the treated group from stage 3 to stage 2 CKD according to the IRIS staging system. Histopathology of renal tissue revealed improving CKD lesions by increasing regeneration of degenerated tubules, maintaining the integrity of glomeruli. New vascularization with blood vessels remodeling were common findings. Periodic acid Schiff stain of renal tissue showed the integrity of renal tubules and thickness of the glomerular basement membrane. Fibrosis of cortex and medulla was lower in the treated group than in the CKD model as monitored by Mallory’s trichrome stain (MTC). NGAL and KIM-1 genes expression were decreased while VEGF and EGF genes expression were increased indicating renal tissue repair.
Liver Disease Mesenchymal stem cells-based therapy in liver diseases
Heng-Tong Han
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
Liver Disease Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases
Chenxia Hu et al.
Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.
Liver Disease Progress in mesenchymal stem cell–based therapy for acute liver failure
Yong-Hong Wang et al.
Acute liver failure is a life-threatening clinical syndrome characterized by rapid development of hepatocellular necrosis leading to high mortality and resource costs. Numerous treatment strategies for acute liver failure simply prevent complications and decelerate disease progression. The only curative treatment for acute liver failure is liver transplantation, but there are many restrictions on the application of liver transplantation. In recent years, a growing number of studies have shown that stem cells can effectively treat acute liver failure. Several types of stem cells have been used to study liver diseases; mesenchymal stem cells are most commonly used because they are easy to obtain and present no ethical problems. The aims of this article are to review the current knowledge regarding therapeutic mechanisms of mesenchymal stem cells in acute liver failure, to discuss recent advancements in preclinical and clinical studies in the treatment of mesenchymal stem cells, and to summarize the methodological improvement of mesenchymal stem cell transplantation in treating liver failure.
Liver Disease Stem cell transplantation for treating liver diseases: progress and remaining challenges
Shanshan Li et al.
With the development of regenerative medicine, various stem cells are increasingly considered for treating liver diseases. Various stem cells have been reported to play an essential role in liver recovery, and studies have verified the preliminary effectiveness and safety of these therapies. Stem cell-based therapies will emerge as an effective treatment strategy for liver diseases. Thus, the research progress and challenges to the related stem cells were reviewed, namely the classification of stem cells, cell culture, transplantation, cell tracing in the body, therapies for various liver diseases.
Liver Disease Stem Cell-Based Therapies for Liver Diseases: An Overview and Update
Jie Wang, et al.
Liver disease is one of the top causes of death globally. Although liver transplantation is a very effective treatment strategy, the shortage of available donor organs, waiting list mortality, and high costs of surgery remain huge problems. Stem cells are undifferentiated cells that can differentiate into a variety of cell types. Scientists are exploring the possibilities of generating hepatocytes from stem cells as an alternative for the treatment of liver diseases.
Liver Disease Systematic review: the effects of autologous stem cell therapy for patients with liver disease
J. K. Moore et al.
As morbidity and mortality from liver disease continues to rise, new strategies are necessary. Liver transplantation is not only an expensive resource committing the patient to lifelong immunosuppression but also suitable donor organs are in short supply. Against this background, autologous stem cell therapy has emerged as a potential treatment option.
Liver Disease Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies
Zaid Al-Dhamin et al.
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
Treatment of the end Stage Liver Cirrhosis by
Human Umbilical Cord Blood Stem Cells:
1. Introduction
The liver is a vital organ essential for life of vertebrates and other animals and plays a
variety of metabolic functions, including glycogen storage, detoxification, plasma protein
synthesis, the production of biochemicals for digestion and other roles. In the normal liver,
hepatocytes physiologically renewed at very slow tempo. However, when injured by acute
damage or drug intoxications, dormant hepatocytes re-enter the cell cycle and hepatic
progenitor cells (HPCs) or oval cells are also thought to differentiate into hepatocytes,
resulting in restoration of the structure and functions of the liver parenchyma (1-2): thus the
liver has regenerative capacity. In severely overwhelmed cases, mature hepatocytes seemed
to be blocked their proliferation activity, but HPCs are thought to be profoundly activated
and play an important role in compensation of liver function (3, 4). When liver injury and
inflammation occur chronically, normal liver tissue is replaced by fibrosis, scare tissue,
diffuse necrosis and regenerative nodules (5), thus resulting in an irreversible chronic
inflammation loss of liver function at the final stage: liver cirrhosis (LC) (6, 7, 8, 9).
Regardless of its underlying causes, the morphologic figures and complications caused by
LC are similar and as disease progresses, complications develop. They include portal
hypertension, varix, ascities, hepatic encephalopathy, idiopathic peritonitis and hepatic
coma. The classification of LC is based on the etiology, such as alcoholics, post-hepatitic,
biliary, cardiac, metabolic, inherited and drug induced cirrhosis. Incidence of the specific
types of liver cirrhosis is different from area to areas. Alcoholic cirrhosis is the most
common type in North America, Western Europe and South America. Abstinence from
alcohol would prevent the complicating liver cirrhosis (10). One-fourth of the patients with
repeated liver injuries and three fourth of post-hepatitic cirrhosis has the history of viral
hepatitis (hepatitis B or hepatitis C)
Lupus Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus
Jianyong Xu et al.
Although mesenchymal stem cells might have potential for treating SLE, their immunoregulatory plasticity renders their therapeutic effects unpredictable. The authors genetically modified mesenchymal stem cells to overexpress IL-37—a protein with immunosuppressive activity—and assessed the modified cells’ effects on immune suppression in vitro, as well as the effects of transplanting such cells into a mouse model of SLE. Mice transplanted with IL-37–overexpressing cells displayed improved survival and reduced signs of SLE compared with controls. Expression of IL-37 by mesenchymal stem cells can maintain higher serum levels of IL-37, and these cells had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. The additive therapeutic effects of this approach might offer a way to enhance the stability and effectiveness of mesenchymal stem cells in treating SLE.
Lupus Allogeneic Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus Erythematosus: 4 Years of Experience
Dandan Wang et al.
Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitors and are capable of differentiating into several tissues of mesenchymal origin. We have shown that bone marrow-derived MSCs from both SLE patients and lupus-prone MRL/lpr mice are defective structurally and functionally. Here we observe the long-term safety and efficacy of allogeneic MSC transplantation (MSCT) in treatment-resistant SLE patients. Eighty-seven patients with persistently active SLE who were refractory to standard treatment or had life-threatening visceral involvement were enrolled. Allogeneic bone marrow or umbilical cord-derived MSCs were harvested and infused intravenously (1 × 106 cells/kg of body weight). Primary outcomes were rates of survival, disease remission and relapse, as well as transplantation-related adverse events. Secondary outcomes included SLE disease activity index (SLEDAI) and serologic features. During the 4-year follow-up and with a mean follow-up period of 27 months, the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87). Disease activity declined as revealed by significant changes in the SLEDAI score, levels of serum autoantibodies, albumin, and complements. A total of five patients (6%) died after MSCT from non-treatment-related events in the 4-year follow-up, and no transplantation-related adverse event was observed. Allogeneic MSCT resulted in the induction of clinical remission and improvement in organ dysfunction in drug-resistant SLE patients.
Lupus Human umbilical cord mesenchymal stem cells derived extracellular vesicles regulate acquired immune response of lupus mouse in vitro
Min Xie, Cuifang Li, Zhou She, Feifeng Wu, Jueyi Mao, Marady Hun, Senlin Luo, Wuqing Wan, Jidong Tian, and Chuan Wen
Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple systems. Immunopathology believes that abnormal T cell function and excessive production of autoantibodies by B cells are involved in multi-organ damage. Human umbilical cord mesenchymal stem cells (hUCMSCs) therapies have endowed with promise in SLE, while the function of MSC-derived extracellular vesicles (MSC-EVs) was still unclear. Extracellular vesicles (EVs) are subcellular components secreted by a paracellular mechanism and are essentially a group of nanoparticles. EVs play a vital role in cell-to-cell communication by acting as biological transporters. New evidence has shown beneficial effects of MSC-EVs on autoimmune diseases, such as their immunomodulatory properties. In this study, we investigated whether hUCMSCs derived extracellular vesicles (hUCMSC-EVs) could regulate abnormal immune responses of T cells or B cells in SLE. We isolated splenic mononuclear cells from MRL/lpr mice, a classical animal model of SLE. PBS (Phosphate-buffered saline), 2 × 105 hUCMSCs, 25 µg/ml hUCMSC-EVs, 50 µg/ml hUCMSC-EVs were co-cultured with 2 × 106 activated splenic mononuclear cells for 3 days in vitro, respectively. The proportions of CD4+ T cell subsets, B cells and the concentrations of cytokines were detected. Both hUCMSCs and hUCMSC-EVs inhibited CD4+ T cells, increased the production of T helper (Th)17 cells, promoted the production of interleukin (IL)-17 and transforming growth factor beta1 (TGF-β1) (P 0.05); only hUCMSCs inhibited CD19+ B cells, promoted the production of interferon-gamma (IFN-γ) and IL-4 (P < 0.05). hUCMSCs exert immunoregulatory effects on SLE at least partially through hUCMSC-EVs in vitro, therefore, hUCMSC-EVs play novel and potential regulator roles in SLE.
Lupus Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients
Xinran Yuan et al.
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.
Lupus Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus
Lingyun Sun, Dandan Wang, Jun Liang, Huayong Zhang, Xuebing Feng, Hong Wang, Bingzhu Hua, Bujun Liu, Shengqin Ye, Xiang Hu, Wenrong Xu, Xiaofeng Zeng, Yayi Hou, Gary S. Gilkeson, Richard M. Silver, Liwei Lu, Songtao Shi
Umbilical cord (UC)–derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE).
Umbilical Cord Mesenchymal Stem Cell Transplantation in
Severe and Refractory Systemic Lupus Erythematosus
Objective. Umbilical cord (UC)–derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies,
based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC
MSC transplantation (MSCT) in human autoimmune
disease. This study was undertaken to assess the efficacy
and safety of allogeneic UC MSCT in patients with
severe and treatment-refractory systemic lupus erythematosus (SLE).
Lupus Allogeneic Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus Erythematosus: 4 Years of Experience
Dandan Wang et al.
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.
Lupus Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients
Xinran Yuan et al.
Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.
Lupus Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study
Dandan Wang et al.
In our present single-center pilot study, umbilical cord (UC)–derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE). The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.
Lyme Disease Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease
Geeta Shroff
Therapy with hESCs might emerge as an effective and safe treatment for patients with both MS and LD. Well-designed clinical trials and follow-up studies are needed to prove the long-term efficacy and safety of hESC therapy in the treatment of patients with MS and LD.
Lyme DiseaseSingle-photon emission tomography imaging in patients with Lyme disease treated with human embryonic stem cells
Geeta Shroff
The purpose of this study was to evaluate the longitudinal changes in brain perfusion in patients with Lyme disease treated with human embryonic stem cells.
Lyme DiseaseTransplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease
Geeta Shroff
Therapy with hESCs might emerge as an effective and safe treatment for patients with both MS and LD. Well-designed clinical trials and follow-up studies are needed to prove the long-term efficacy and safety of hESC therapy in the treatment of patients with MS and LD.
Mesenchymal Stem Cells Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases
Jae-Sung Ryu et al.
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.
Mesenchymal Stem Cells Extracellular vesicles derived from Wharton’s Jelly mesenchymal stem cells inhibit the tumor environment via the miR-125b/HIF1α signaling pathway
Yun-Hsuan Chang
Triple negative breast cancer (TNBC) is associated with worse outcomes and results in high mortality; therefore, great efforts are required to find effective treatment. In the present study, we suggested a novel strategy to treat TNBC using mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) to transform the behaviors and cellular communication of TNBC cells (BCC) with other non-cancer cells related to tumorigenesis and metastasis. Our data showed that, BCC after being internalized with EV derived from Wharton’s Jelly MSC (WJ-EV) showed the impaired proliferation, stemness properties, tumorigenesis and metastasis under hypoxic conditions. Moreover, these inhibitory effects may be involved in the transfer of miRNA-125b from WJ-EV to BCC, which downregulated the expression of HIF1α and target genes related to proliferation, epithelial-mesenchymal transition, and angiogenesis.
Mesenchymal Stem Cells Mesenchymal stromal cells: sensors and switchers of inflammation
Maria Ester Bernardo, Willem E Fibbe
In addition to their stem/progenitor properties, mesenchymal stromal cells (MSCs) possess broad immunoregulatory properties that are being investigated for potential clinical application in treating immune-based disorders. An informed view of the scope of this clinical potential will require a clear understanding of the dynamic interplay between MSCs and the innate and adaptive immune systems. In this Review, we outline current insights into the ways in which MSCs sense and control inflammation, highlighting the central role of macrophage polarization. We also draw attention to functional differences seen between vivo and in vitro contexts and between species. Finally, we discuss progress toward clinical application of MSCs, focusing on GvHD as a case study.
Mesenchymal Stem Cells Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy
Xing-Liang Fan et al.
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of
Secondary Progressive Multiple Sclerosis
Abstract
Background: Multiple sclerosis (MS) is an irreversible and demyelinating disease of the brain and spinal cord
that causes signifcant disability in young people. However, therapeutic options to effectively stop the pathological
progression of MS are limited. This study aimed to evaluate the safety and effcacy of human umbilical cord-derived
mesenchymal stem cells (hUC-MSCs) in the treatment of secondary progressive multiple sclerosis.
Mesenchymal stem cells and kidney repair
ABSTRACT
Acute renal failure (ARF; acute kidney injury—according to
the more recent classification) is emerging as a public health
problem. Despite major advances in supportive therapy, the
mortality and morbidity among patients remain dismally
high. In the attempt to yield innovative interventions fostering the limited capability of regeneration of the kidney,
several studies have tested stem cell-based technology mainly
employing mesenchymal stem cells (MSC) of different
origins. The results of this approach provide the exciting prospect of a powerful treatment to repair acutely damaged
organs by virtue of the unique MSC tropism for the damaged
tissue, as well as their paracrine action. In the present review,
we discuss the mechanisms underlying the regenerative processes triggered by MSC therapy in preclinical models of ARF
by analysing modalities of cell-to-cell communication
through the release of soluble factors and microvesicles/exosomes by MSC into the damaged renal tissue. Key receptors
involved in MSC homing, engraftment and survival at the
sites of injury are also elucidated. A translation of basic discoveries of MSC biology into effective care is still limited to
the preliminary data of a phase I clinical trial, and further
studies are needed to definitively assess the efficacy of MSCbased therapy in humans.
Mesenchymal stem cells in arthritic diseases
Abstract
Mesenchymal stem cells (MSCs), the nonhematopoietic progenitor
cells found in various adult tissues, are characterized by their ease
of isolation and their rapid growth in vitro while maintaining their
differentiation potential, allowing for extensive culture expansion to
obtain large quantities suitable for therapeutic use. These
properties make MSCs an ideal candidate cell type as building
blocks for tissue engineering efforts to regenerate replacement
tissues and repair damaged structures as encountered in various
arthritic conditions. Osteoarthritis (OA) is the most common
arthritic condition and, like rheumatoid arthritis (RA), presents an
inflammatory environment with immunological involvement and this
has been an enduring obstacle that can potentially limit the use of
cartilage tissue engineering. Recent advances in our understanding
of the functions of MSCs have shown that MSCs also
possess potent immunosuppression and anti-inflammation effects.
In addition, through secretion of various soluble factors, MSCs can
influence the local tissue environment and exert protective effects
with an end result of effectively stimulating regeneration in situ.
This function of MSCs can be exploited for their therapeutic
application in degenerative joint diseases such as RA and OA. This
review surveys the advances made in the past decade which have
led to our current understanding of stem cell biology as relevant to
diseases of the joint.
Comparable therapeutic potential of umbilical cord
mesenchymal stem cells in collagen-induced arthritis
to TNF inhibitor or anti-CD20 treatment
Abstract
Objective
The ejfects ofmesenchymal stem cell (MSC) transplantation on established collagen-induced arthritis (CIA) were
evaluated and compared to biologic therapies.
Mesenchymal Stem Cells
Reduce Murine Atherosclerosis
Development
Obstract :
Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found
to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce
atherosclerosis, which is determined by dyslipidaemia and chronic infammation. We adoptively
transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a
Westerntype diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating
regulatory T cells. In the long-term, overall numbers of efector T cells were reduced by MSC
treatment. Moreover, MSC-treated mice displayed a signifcant 33% reduction in circulating
monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously
unappreciated efect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced
very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as
determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs
signifcantly afected lesion development, which was reduced by 33% in the aortic root. These lesions
contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for
the frst time that MSC treatment afects not only infammatory responses but also signifcantly
reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies.
Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders
Obstract:
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate
into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identifed
at different stages of development, including adulthood, and in different tissues, such as bone marrow,
adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to
injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and
antiinfammatory effects. For instance, there is evidence that MSCs can regulate the immune system by
inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably
over the past few years, especially because of the ideal characteristics of these cells for regenerative
medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition
to regulating infammation, they can promote other benefcial effects, such as neuronal growth, decrease
free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in
neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarifed, hindering
the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce,
despite the promising results of MSCs therapies in this feld as well.
Key words: Mesenchymal stem cells, treatment, neurodegenerative disease, psychiatric disorders.
Our objective was to evaluate the feasibility, safety, and efficacy of intravenous (IV) infusion of allogenic mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) patients who are refractory to or cannot tolerate
the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). AS patients enrolled in this study received
four IV infusions of MSCs on days 0, 7, 14, and 21. The percentage of ASAS20 responders (the primary
endpoint) at the fourth week and the mean ASAS20 response duration (the secondary endpoint) were used
to assess treatment response to MSC infusion and duration of the therapeutic effects. Ankylosing Spondylitis
Disease Activity Score Containing C-reactive Protein (ASDAS-CRP) and other preestablished evaluation indices were also adopted to evaluate the clinical effects. Magnetic resonance imaging (MRI) was performed to
detect changes of bone marrow edema in the spine. The safety of this treatment was also evaluated. Thirty-one
patients were included, and the percentage of ASAS20 responders reached 77.4% at the fourth week, and the
mean ASAS20 response duration was 7.1 weeks. The mean ASDAS-CRP score decreased from 3.6±0.6 to
2.4±0.5 at the fourth week and then increased to 3.2±0.8 at the 20th week. The average total inflammation
extent (TIE) detected by MRI decreased from 533,482.5 at baseline to 480,692.3 at the fourth week (p>0.05)
and 400,547.2 at the 20th week (p<0.05). No adverse effects were noted. IV infusion of MSCs is a feasible,
safe, and promising treatment for patients with AS.
Key words: Ankylosing spondylitis (AS); Autoimmune; Mesenchymal stem cells (MSCs);
Nonsteroidal anti-inflammatory drugs (NSAIDs)
View study
Potential of Mesenchymal Stem Cell based
ABSTRACT
Stem cell based treatments are being increasingly explored for their possible potential to treat various
cancers. Mesenchymal stem cells believed to possess anti-tumor potential and are preferred for their
properties like immune privileged nature, ability to migrate to the site of tumor and capability for multilineage
differentiation. This tumor tropism property of MSCs could be utilized to deliver anti-tumor biological agents to
the site of tumor. In a tumor micro-environment, MSCs are believed to play both, a pro-tumorigenic and an
anti-tumorigenic role. However, this is dependent on a host of factors like, types of MSCs, its source, type of
cancer cell line under investigation, in vivo or in vitro conditions, factors secreted by MSCs and interactions
between MSCs, host’s immune cells and cancer cells. Among several cytokines secreted by MSCs, TRAIL
(Tumor necrosis factor related apoptosis inducing ligand) is reported to be pro-apoptotic for tumor cells.
The MSCs from bone marrow and adipose tissue have been studied quite extensively. Deriving MSCs from
sources such as umbilical cord blood and umbilical cord tissue is relatively easier. Umbilical cord tissue
preferred for MSC derivation due to their abundant availability. These MSCs believed to up regulate TRAIL
expression in MSC-cancer cell co-culture system resulting in induction of apoptosis in cancer cells. However,
umbilical cord tissue derived MSCs needs to be studied for expression pattern of TRAIL in a co-culture system.
We present a revie
Abstract
Background: Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human
allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair.
Methods: This is a randomized, double-blinded, dose-fnding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered
to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TESAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of
frailty measured at 6 months postinfusion.
Results: No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic
improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory
volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire
improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in
both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.
View study
Multiple Sclerosis Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study
Peter Connick et al.
More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.
Multiple Sclerosis Mesenchymal Stem Cells and Induced Pluripotent Stem Cells as Therapies for Multiple Sclerosis
Juan Xiao et al.
Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS.
Multiple Sclerosis Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Pre-Clinical to Clinical Studies
Agnese Gugliandolo, Placido Bramanti, and Emanuela Mazzon
Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Nowadays, available therapies for MS can help to manage MS course and symptoms, but new therapeutic approaches are required. Stem cell therapy using mesenchymal stem cells (MSCs) appeared promising in different neurodegenerative conditions, thanks to their beneficial capacities, including the immunomodulation ability, and to their secretome. The secretome is represented by growth factors, cytokines, and extracellular vesicles (EVs) released by MSCs. In this review, we focused on studies performed on in vivo MS models involving the administration of MSCs and on clinical trials evaluating MSCs administration. Experimental models of MS evidenced that MSCs were able to reduce inflammatory cell infiltration and disease score. Moreover, MSCs engineered to express different genes, preconditioned with different compounds, differentiated or in combination with other compounds also exerted beneficial actions in MS models, in some cases also superior to native MSCs. Secretome, both conditioned medium and EVs, also showed protective effects in MS models and appeared promising to develop new approaches. Clinical trials highlighted the safety and feasibility of MSC administration and reported some improvements, but other trials using larger cohorts of patients are needed.
Multiple Sclerosis Safety and efficacy of stem cell therapy for treatment of neural damage in patients with multiple sclerosis
Mohammadmahdi Jafarzadeh Bejargafshe et al.
Multiple sclerosis (MS) is a multifocal inflammatory disease that involves the central nervous system and associated with limbs paralysis and serious problems in sensation, limbs, visual and sphincter. This disease is a result of autoimmune mechanism in which autoantibodies target the self-myelin antigens and cause demyelination. Because of the myelin dysfunction, MS is clinically identified with neurological disabilities. Furthermore, it can be entered into the progressive phase because of irreversible neurodegeneration and axons damage. Unfortunately, there is no effective therapeutic method for this disease and current medications have been focused on amelioration of symptoms and chronic inflammation. Although current immunotherapies ameliorate the reactivity of autoimmune anti-myelin and MS relapse rate, there is no approved method for improvement of the disease progression and repairing of the damaged myelin. Therefore, finding an appropriate clinical treatment for improvement of neurological damages in MS patients is essential. Mesenchymal stem cells (MSCs) are multipotent cells with high proliferative and self-renewal capacities, as well as immunomodulatory and neuroregenerative effects. Bone marrow and adipose tissues derived MSCs have been considered for the treatment of different diseases because not only they can be easily isolated from these tissues, but also a patient can be served as a donor for himself without the risk of rejection. More importantly, autologous MSCs carry a safer pattern without the risk of malignant transformation. Here, we will discuss the effectiveness of MSCs therapy for MS patients by reviewing of clinical trials.
These data suggest that combined intravenous and intrathecal low-dose hUC-MSCs transplantation is safe and feasible in RRMS and NMO patients in the long term. The conclusion requires confirmation by future clinical trials in a larger cohort.
Multiple Sclerosis Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis
Isabela Morales et al.
Multiple sclerosis (MS) is a progressively debilitating neurological condition in which the immune system abnormally erodes the myelin sheath insulating the nerves. Mesenchymal stem cells (MSC) have been used in the last decade to safely treat certain immune and inflammatory conditions.
Multiple Sclerosis Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders
Alexander Markov et al.
Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn’s disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.
Multiple Sclerosis Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases
Nathan P. Staff, M.D et al.
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson’s disease, and Alzheimer’s disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward side effects.
Multiple Sclerosis The potential use of mesenchymal stem cells for the treatment of multiple sclerosis
Sahar Rostami Mansoor et al.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS). In attempt to identify an appropriate treatment for improving the neurological symptoms and remyelination process, autologous and allogenic transplantation of mesenchymal stem cells (MSCs) have been introduced as an effective therapeutic strategy in MS. MSCs are a heterogeneous subset of pluripotent non-hematopoietic stromal cells that are isolated from bone marrow, adipose tissue, placenta and other sources. MSCs have considerable therapeutic effects due to their ability in differentiation, migration, immune-modulation and neuroregeneration. To date, numerous experimental and clinical studies demonstrated that MSCs therapy improves the CNS repair and modulates functional neurological symptoms. Here, we provided an overview of the current knowledge about the clinical applications of MSCs in MS. Furthermore, the major challenges and risks of MSCs therapy in MS patients have been elucidated.
Multiple SclerosisThe Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells as a Novel Cellular Therapy for Multiple SclerosisThe Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells as a Novel Cellular Therapy for Multiple Sclerosis
Jin-Feng Li et al.
Multiple sclerosis (MS) is a complex disease of neurological disability, affecting more than 300 out of every 1 million people in the world. The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MS patients. Twenty-three patients were enrolled in this study, and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone intravenously (IV) daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1 mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5 mg every 2 weeks until reaching a 5-mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6-week period for each patient. The overall symptoms of the hUC-MSC-treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC-treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS.
Journal of Stem Cell Research & Therapy
Clinical efficacy and safety of mesenchymal
stem cell transplantation for osteoarthritis
Abstract
Purpose
The aim of this study was to evaluate the therapeutic efficacy and safety of mesenchymal
stem cells (MSCs) for the treatment of patients with knee osteoarthritis (OA).
Parkinson’s Disease (PD) is an intractable disease resulting in localized neurodegeneration of dopaminergic neurons of the substantia nigra pars compacta. Many current therapies of PD can only address the symptoms and not the underlying neurodegeneration of PD. To better understand the pathophysiological condition, researchers continue to seek models that mirror PD’s phenotypic manifestations as closely as possible. Recent advances in the field of cellular reprogramming and personalized medicine now allow for previously unattainable cell therapies and patient-specific modeling of PD using induced pluripotent stem cells (iPSCs). iPSCs can be selectively differentiated into a dopaminergic neuron fate naturally susceptible to neurodegeneration. In iPSC models, unlike other artificially-induced models, endogenous cellular machinery and transcriptional feedback are preserved, a fundamental step in accurately modeling this genetically complex disease. In addition to accurately modeling PD, iPSC lines can also be established with specific genetic risk factors to assess genetic sub-populations’ differing response to treatment. iPS cell lines can then be genetically corrected and subsequently transplanted back into the patient in hopes of re-establishing function. Current techniques focus on iPSCs because they are patient-specific, thereby reducing the risk of immune rejection. The year 2018 marked history as the year that the first human trial for PD iPSC transplantation began in Japan. This form of cell therapy has shown promising results in other model organisms and is currently one of our best options in slowing or even halting the progression of PD. Here, we examine the genetic contributions that have reshaped our understanding of PD, as well as the advantages and applications of iPSCs for modeling disease and personalized therapies.
Parkinson’s Mesenchymal Stem Cells as a Source of Dopaminergic Neurons: A Potential Cell Based Therapy for Parkinson’s Disease
Katari Venkatesh, Dwaipayan Sen
Cell repair/replacing strategies for neurodegenerative diseases such as Parkinson’s disease depend on well-characterized dopaminergic neuronal candidates that are healthy and show promising effect on the rejuvenation of degenerated area of the brain. Therefore, it is imperative to develop innovative therapeutic strategies that replace damaged neurons with new/functional dopaminergic neurons. Although several research groups have reported the generation of neural precursors/neurons from human/ mouse embryonic stem cells and mesenchymal stem cells, the latter is considered to be an attractive therapeutic candidate because of its high capacity for self-renewable, no adverse effect to allogeneic versus autologous transplants, high ethical acceptance and no teratoma formation. Therefore, mesenchymal stem cells can be considered as an ideal source for replacing lost cells in degenerative diseases like Parkinson’s. Hence, the use of these cells in the differentiation of dopaminergic neurons becomes significant and thrives as a therapeutic approach to treat Parkinson’s disease. Here we highlight the basic biology of mesenchymal stem cells, their differentiation potential into dopaminergic neurons and potential use in the clinics.
Parkinson’s Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases
Nathan P. Staff et al.
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson’s disease, and Alzheimer’s disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward side effects.
Parkinson’s Pluripotent Stem Cell-based therapy for Parkinson’s disease: current status and future prospects
Kai-C. Sonntag et al.
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which affects about 0.3% of the general population. As the population in the developed world ages, this creates an escalating burden on society both in economic terms and in quality of life for these patients and for the families that support them. Although currently available pharmacological or surgical treatments may significantly improve the quality of life of many patients with PD, these are symptomatic treatments that do not slow or stop the progressive course of the disease. Because motor impairments in PD largely result from loss of midbrain dopamine neurons in the substantia nigra pars compacta, PD has long been considered to be one of the most promising target diseases for cell-based therapy. Indeed, numerous clinical and preclinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells as a standardized therapeutic regimen has been fraught with fundamental ethical, practical, and clinical issues, prompting scientists to explore alternative cell sources. Based on groundbreaking establishments of human embryonic stem cells and induced pluripotent stem cells, these human pluripotent stem cells have been the subject of extensive research, leading to tremendous advancement in our understanding of these novel classes of stem cells and promising great potential for regenerative medicine. In this review, we discuss the prospects and challenges of human pluripotent stem cell-based cell therapy for PD.
Parkinson’s Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration
Cristina Angeloni et al.
Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.
Cell replacement therapy (CRT) offers great promise as the future of regenerative medicine in Parkinson´s disease (PD). Three decades of experiments have accumulated a wealth of knowledge regarding the replacement of dying neurons by new and healthy dopaminergic neurons transplanted into the brains of animal models and affected patients. The first clinical trials provided the proof of principle for CRT in PD. In these experiments, intrastriatal transplantation of human embryonic mesencephalic tissue reinnervated the striatum, restored dopamine levels and showed motor improvements. Sequential controlled studies highlighted several problems that should be addressed prior to the wide application of CRT for PD patients. Moreover, owing to ethical and practical problems, embryonic stem cells require replacement by better-suited stem cells. Several obstacles remain to be surpassed, including identifying the best source of stem cells for A9 dopaminergic neuron generation, eliminating the risk of tumor formation and the development of graft-induced dyskinesias, and standardizing dopaminergic cell production in order to enable clinical application. In this article, we present an update on CRT for PD, reviewing the research milestones, various stem cells used and tailored differentiation methods, and analyze the information gained from the clinical trials.
Parkinson’s Disease A New Tool for Safety Evaluation and a Combination of Measures for Efficacy Assessment of Cotransplanting Human Allogenic Neuronal Stem Cells and Mesenchymal Stem Cells for the Treatment of Parkinson Disease: Protocol for an Interventional Study
Fatima Jamali, PhD, Mayis Aldughmi, PhD, Mohammad W Khasawneh, MD, Said Dahbour, MD, Alaa A Salameh, MSc, PT, and Abdalla Awidi, MD
The combination of NSCs and MSCs in PD may be useful for harnessing the best of the immunomodulation and neural repair characteristics of these cell types. The tailored comprehensive and scaled TEAEs and the variety of evaluation tools used enables a comprehensive assessment of this cellular therapy treatment protocol. A consideration of this expanded tool set is important in the design of future clinical studies for PD.
Parkinson’s Disease A New Tool for Safety Evaluation and a Combination of Measures for Efficacy Assessment of Cotransplanting Human Allogenic Neuronal Stem Cells and Mesenchymal Stem Cells for the Treatment of Parkinson Disease: Protocol for an Interventional Study
Fatima Jamali, Mayis Aldughmi, Mohammad W Khasawneh, Said Dahbour, Alaa A Salameh, Abdalla Awidi
The combination of NSCs and MSCs in PD may be useful for harnessing the best of the immunomodulation and neural repair characteristics of these cell types. The tailored comprehensive and scaled TEAEs and the variety of evaluation tools used enables a comprehensive assessment of this cellular therapy treatment protocol. A consideration of this expanded tool set is important in the design of future clinical studies for PD.
Parkinson’s Disease Allogeneic Bone Marrow–Derived Mesenchymal Stem Cell Safety in Idiopathic Parkinson’s Disease
Mya Schiess, MD, Jessika Suescun, MD, Marie‐Francoise Doursout, PhD, Christopher Adams, MD, Charles Green, PhD, Jerome G. Saltarrelli, PhD, Sean Savitz, MD, and Timothy M. Ellmore, PhD
Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis of PD is based on the presence of impaired motor features such as asymmetric or unilateral resting tremor, bradykinesia, and rigidity. Nonmotor features including cognitive impairment, sleep disorders, and autonomic dysfunction are also present. No cure for PD has been discovered, and treatment strategies focus on symptomatic management through restoration of dopaminergic activity. However, proposed cell replacement therapies are promising because midbrain dopaminergic neurons have been shown to restore dopaminergic neurotransmission and functionally rescue the dopamine-depleted striatum. In this review, we summarize our current understanding of the molecular pathogenesis of neurodegeneration in PD and discuss the development of new therapeutic strategies that have led to the initiation of exploratory clinical trials. We focus on the applications of stem cells for the treatment of PD and discuss how stem cell research has contributed to an understanding of PD, predicted the efficacy of novel neuroprotective therapeutics, and highlighted what we believe to be the critical areas for future research.
Parkinson’s DiseaseMesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine
Silvia Fernández-Francos, Noemi Eiro, Luis A. Costa, Sara Escudero-Cernuda, María Luisa Fernández-Sánchez, Francisco J. Vizoso
Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.
Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, and as a consequence, by decreased dopamine levels in the striatum. Currently available therapies are not able to stop or reverse the progression of the disease. A novel therapeutic approach is based on cell therapy with stem cells, in order to replace degenerated neurons. Among stem cells, mesenchymal stem cells seemed the most promising thanks to their capacities to differentiate toward dopaminergic neurons and to release neurotrophic factors. Indeed, mesenchymal stem cells are able to produce different molecules with immunomodulatory, neuroprotective, angiogenic, chemotactic effects and that stimulate differentiation of resident stem cells. Mesenchymal stem cells were isolated for the first time from bone marrow, but can be collected also from adipose tissue, umbilical cord and other tissues. In this review, we focused our attention on mesenchymal stem cells derived from different sources and their application in Parkinson’s disease animal models.
Primary Biliary Cirrhosis Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis
Lifeng Wang et al.
UC-MSC transfusion is feasible and well tolerated in patients with PBC who respond only partially to UDCA treatment, thus representing a novel therapeutic approach for patients in this subgroup. A larger, randomized controlled cohort study is warranted to confirm the clinical efficacy of UC-MSC transfusion.
Therapeutic potential of human umbilical cord
mesenchymal stem cells in the treatment of
rheumatoid arthritis
Abstract
Introduction: Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by
synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective
in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord
(UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were
evaluated.
Rheumatoid Arthritis Efficacy and Safety of Umbilical Cord Mesenchymal Stem Cell Therapy for Rheumatoid Arthritis Patients: A Prospective Phase I/II Study
Liming Wang et al.
The traditional anti-inflammation disease-modifying anti-rheumatic drugs (DMARDs) have limited therapeutic effects in rheumatoid arthritis (RA) patients. We previously reported the safety and efficacy of umbilical cord mesenchymal stem cell (UC-MSC) treatment in RA patients that were observed for up to 8 months after UC-MSC infusion. The aim of this study is to assess the long-term efficacy and safety of UC-MSC along with DMARDs for the treatment of RA.
Rheumatoid Arthritis Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy
Liming Wang et al.
This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or DMARDs plus UC-MSCs group (4×10(7) cells per time) via intravenous injection. Adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted. Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor-alpha and interleukin-6 decreased after the first UC-MSCs treatment (P<0.05). The percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells of peripheral blood was increased (P<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology improvement criteria, the 28-joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects maintained for 3-6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In comparison, there were no such benefits observed in control group of DMARDS plus medium without UC-MSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and persistent clinical benefits for patients with active RA.
Rheumatoid Arthritis Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis
Yanying Liu et al.
In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.
Human Umbilical Cord Mesenchymal Stem Cell Therapy
for Patients with Active Rheumatoid Arthritis:
Safety and Efficacy
Liming Wang,1* Lihua Wang,2* Xiuli Cong,3 Guangyang Liu,3 Jianjun Zhou,1 Bin Bai,1 Yang Li,1
Wen Bai,1 Ming Li,1 Haijie Ji,3 Delin Zhu,3 Mingyuan Wu,4,5 and Yongjun Liu3,5
This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UCMSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who
had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for
different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or
DMARDs plus UC-MSCs group (4 · 107 cells per time) via intravenous injection. Adverse events and the clinical
information were recorded. Tests for serological markers to assess safety and disease activity were conducted.
Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral
blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of
tumor necrosis factor-alpha and interleukin-6 decreased after the first UC-MSCs treatment (P < 0.05). The percentage of CD4 +CD25 + Foxp3 + regulatory T cells of peripheral blood was increased (P < 0.05). The treatment
induced a significant remission of disease according to the American College of Rheumatology improvement
criteria, the 28-joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects
maintained for 3–6 months without continuous administration, correlating with the increased percentage of
regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In
comparison, there were no such benefits observed in control group of DMARDS plus medium without UCMSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and
persistent clinical benefits for patients with active RA.
View study
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects the lining of the synovial joints leading to stiffness, pain, inflammation, loss of mobility, and erosion of joints. Its pathogenesis is related to aberrant immune responses against the synovium. Dysfunction of innate and adaptive immunity, including dysregulated cytokine networks and immune complex-mediated complement activation, are involved in the progression of RA. At present, drug treatments, including corticosteroids, antirheumatic drugs, and biological agents, are used in order to modulate the altered immune responses. Chronic use of these drugs may cause adverse effects to a significant number of RA patients. Additionally, some RA patients are resistant to these therapies. In recent years, mesenchymal stem/stromal cell (MSCs)-based therapies have been largely proposed as a novel and promising stem cell therapeutic approach in the treatment of RA. MSCs are multipotent progenitor cells that have immunomodulatory properties and can be obtained and expanded easily. Today, nearly one hundred studies in preclinical models of RA have shown promising trends for clinical application. Proof-of-concept clinical studies have demonstrated satisfactory safety profile of MSC therapy in RA patients. The present review discusses MSC-based therapy approaches with a focus on published clinical data, as well as on clinical trials, for treatment of RA that are currently underway.
The pathogenesis of the autoimmune rheumatological diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is complex with the involvement of several immune cell populations spanning both innate and adaptive immunity including different T-lymphocyte subsets and monocyte/macrophage lineage cells. Despite therapeutic advances in RA and SLE, some patients have persistent and stubbornly refractory disease. Herein, we discuss stromal cells’ dual role, including multipotent mesenchymal stromal cells (MSCs) also used to be known as mesenchymal stem cells as potential protagonists in RA and SLE pathology and as potential therapeutic vehicles. Joint MSCs from different niches may exhibit prominent pro-inflammatory effects in experimental RA models directly contributing to cartilage damage. These stromal cells may also be key regulators of the immune system in SLE. Despite these pro-inflammatory roles, MSCs may be immunomodulatory and have potential therapeutic value to modulate immune responses favorably in these autoimmune conditions. In this review, the complex role and interactions between MSCs and the haematopoietically derived immune cells in RA and SLE are discussed. The harnessing of MSC immunomodulatory effects by contact-dependent and independent mechanisms, including MSC secretome and extracellular vesicles, is discussed in relation to RA and SLE considering the stromal immune microenvironment in the diseased joints. Data from translational studies employing MSC infusion therapy against inflammation in other settings are contextualized relative to the rheumatological setting. Although safety and proof of concept studies exist in RA and SLE supporting experimental and laboratory data, robust phase 3 clinical trial data in therapy-resistant RA and SLE is still lacking.
Mesenchymal stem cell (MSC) therapies have been used as cell-based treatments for decades, owing to their anti-inflammatory, immunomodulatory, and regenerative properties. With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat arthritic diseases. Studies on osteoarthritis (OA) have shown positive clinical outcomes, with improved joint function, pain level, and quality of life. In addition, few clinical MSC trials conducted on rheumatoid arthritis (RA) patients have also displayed some optimistic outlook. The largely positive outcomes in clinical trials without severe side effects establish MSCs as promising tools for arthritis treatment. However, further research is required to investigate its applicability in clinical settings. This review discusses the most recent advances in clinical studies on MSC therapies for OA and RA.
Umbilical cord mesenchymal stem cell
transplantation in active and refractory systemic
lupus erythematosus: a multicenter clinical study
Dandan Wang1
Abstract:
Introduction: In our present single-center pilot study, umbilical cord (UC)–derived mesenchymal stem cells (MSCs)
had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE). The
present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation
(MSCT) in patients with active and refractory SLE.
Spinal Cord Injury Treatment of spinal cord injury with mesenchymal stem cells
These characteristics are crucial for the restoration of spinal cord function upon SCI as damaged cord has limited regenerative capacity and it is also something that cannot be achieved by pharmacological and physiotherapy interventions. New biological therapies including stem cell secretome therapy, immunotherapy and scaffolds can be combined with MSC therapy to enhance its therapeutic effects.
Stem Cells in the Umbilical Cord
Abstract:
Stem cells are the next frontier in medicine. Stem cells are thought to have great therapeutic and biotechnological potential. This
will not only to replace damaged or dysfunctional cells, but also rescue them and/or deliver therapeutic proteins after they have
been engineered to do so. Currently, ethical and scientific issues surround both embryonic and fetal stem cells and hinder their
widespread implementation. In contrast, stem cells recovered postnatally from the umbilical cord, including the umbilical cord
blood cells, amnion/placenta, umbilical cord vein, or umbilical cord matrix cells, are a readily available and inexpensive source of
cells that are capable of forming many different cell types (i.e., they are “multipotent”). This review will focus on the umbilical
cord-derived stem cells and compare those cells with adult bone marrow-derived mesenchymal stem cells.
Index Entries: Umbilical cord matrix cells, Wharton’s Jelly, mesenchymal stem cells, umbilical cord blood cells
Stroke Stem Cell Therapy for Abrogating Stroke-Induced Neuroinflammation and Relevant Secondary Cell Death Mechanisms
Stroke
Stem Cell Therapy for Abrogating Stroke-Induced Neuroinflammation and Relevant Secondary Cell Death Mechanisms
Connor Stonesifer et al.
Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.
Stroke Stem Cell Transplantation Therapy for Multifaceted Therapeutic Benefits after Stroke
Ling Wei et al.
One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke.
We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0–3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients. Stem Cells 2010;28:1099–1106
Efficacy of stem cell-based therapies for stroke
Stroke remains a prevalent disease with limited treatment options. Available treatments offer little in the way of enhancing neurogenesis and recovery. Because of the limitations of available treatments, new therapies for stroke are needed. Stem cell-based therapies for stroke offer promise because of their potential to provide neurorestorative benefits. Stem cell-based therapies aim to promote neurogenesis and replacement of lost neurons or protect surviving neurons in order to improve neurological recovery. The mechanism through which stem cell treatments mediate their therapeutic effect is largely dependent on the type of stem cell and route of administration. Neural stem cells have been shown in pre-clinical and clinical trials to promote functional recovery when used in intracerebral transplantations. The therapeutic effects of neural stem cells have been attributed to their formation of new neurons and promotion of neuroregeneration. Bone marrow stem cells (BMSC) and mesenchymal stem cells (MSC) have been shown to enhance neurogenesis in pre-clinical models in intracerebral transplantations, but lack clinical evidence to support this therapeutic approach in patients and appear to be less effective than neural stem cells. Intravenous and intra-arterial administration of BMSC and MSC have shown more promise, where their effects are largely mediated through neuroprotective mechanisms. The immune system has been implicated in exacerbating initial damage caused by stroke, and BMSC and MSC have demonstrated immunomodulatory properties capable of dampening post-stroke inflammation and potentially improving recovery. While still in development, stem cell therapies may yield new treatments for stroke which can improve neurological recovery.
Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36–133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.
Ischemic stroke is the third cause of death in the developed countries and the main reason of severe disability. Brain ischemia leads to the production of damage-associated molecular patterns (DAMPs) by neurons and glial cells which results in astrocyte and microglia activation, pro-inflammatory cytokines and chemokines production, blood-brain barrier (BBB) disruption, infiltration of leukocytes from the peripheral blood into the infarcted area, and further exacerbation of tissue damage. However, some immune cells such as microglia or monocytes are capable to change their phenotype to anti-inflammatory, produce anti-inflammatory cytokines, and protect injured nervous tissue. In this situation, therapies, which will modulate the immune response after brain ischemia, such as transplantation of mesenchymal stem cells (MSCs) are catching interest. Many experimental studies of ischemic stroke revealed that MSCs are able to modulate immune response and act neuroprotective, through stimulation of neurogenesis, oligodendrogenesis, astrogenesis, and angiogenesis. MSCs may also have an ability to replace injured cells, but the release of paracrine factors directly into the environment or via extracellular vesicles (EVs) seems to play the most pronounced role. EVs are membrane structures containing proteins, lipids, and nucleic acids, and they express similar properties as the cells from which they are derived. However, EVs have lower immunogenicity, do not express the risk of vessel blockage, and have the capacity to cross the blood-brain barrier. Experimental studies of ischemic stroke showed that EVs have immunomodulatory and neuroprotective properties; therefore, they can stimulate neurogenesis and angiogenesis. Up to now, 20 clinical trials with MSC transplantation into patients after stroke were performed, from which two concerned on only hemorrhagic stroke and 13 studied only on ischemic stroke. There is no clinical trial with EV injection into patients after brain ischemia so far, but the case with miR-124-enriched EVs administration is planned and probably there will be more clinical studies with EV transplantation in the near future.
Stroke is the most prevalent cardiovascular disease worldwide, and is still one of the leading causes of death and disability. Stem cell-based therapy is actively being investigated as a new potential treatment for certain neurological disorders, including stroke. Various types of cells, including bone marrow mononuclear cells, bone marrow mesenchymal stem cells, dental pulp stem cells, neural stem cells, inducible pluripotent stem cells, and genetically modified stem cells have been found to improve neurological outcomes in animal models of stroke, and there are some ongoing clinical trials assessing their efficacy in humans. In this review, we aim to summarize the recent advances in cell-based therapies to treat stroke.
Stroke Autologous Mesenchymal Stem Cells in Chronic Stroke
Stroke
Autologous Mesenchymal Stem Cells in Chronic Stroke
Ashu Bhasin et al.
Cell transplantation is a ‘hype and hope’ in the current scenario. It is in the early stage of development with promises to restore function in chronic diseases. Mesenchymal stem cell (MSC) transplantation in stroke patients has shown significant improvement by reducing clinical and functional deficits. They are feasible and multipotent and have homing characteristics. This study evaluates the safety, feasibility and efficacy of autologous MSC transplantation in patients with chronic stroke using clinical scores and functional imaging (blood oxygen level-dependent and diffusion tensor imaging techniques).
Therapeutic Potentials of Mesenchymal Stem Cells Derived
from Human Umbilical Cord
Abstract:
Human umbilical cord-derived mesenchymal
stem cells (hUC-MSCs), isolated from discarded extraembryonic
tissue after birth, are promising candidate
source of mesenchymal stem cells (MSCs). Apart from
their prominent advantages in abundant supply, painless
collection, and faster self-renewal, hUC-MSCs have
shown the potencies to differentiate into a variety of
cells of three germ layers (such as bone, cartilage,
adipose, skeletal muscle, cardiomyocyte, endothelium,
hepatocyte-like cluster, islet-like cluster, neuron, astrocyte
and oligodendrocyte), to synthesize and secret a set of
trophic factors and cytokines, to support the expansion and
function of other cells (like hematopoietic stem cells,
embryonic stem cells, natural killer cells, islet-like cell
clusters, neurons and glial cells) , to migrate toward and
home to pathological areas, and to be readily transfected
with conventional methods.
Protein in human umbilical cord
blood rejuvenates old mice’s
impaired learning, memory
Human umbilical cord blood can rejuvenate learning and memory
in older mice, according to a study by researchers at the Stanford
University School of Medicine.
The researchers identified a protein, abundant in human cord
blood but decreasingly so with advancing age, that had the same
effect when injected into the animals.
The findings could lead to new treatments for age-associated
declines in mental ability
Traumatic Brain Injury Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI
Rami Ahmad Shahror,1,2,3,4 Chung-Che Wu,3,4,5,6 Yung-Hsiao Chiang,2,3,4,5,6,* and Kai-Yun Chen
Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs’ biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.
Traumatic brain injury is a major economic burden to hospitals in terms of emergency department visits, hospitalizations, and utilization of intensive care units. Current guidelines for the management of severe traumatic brain injuries are primarily supportive, with an emphasis on surveillance (i.e. intracranial pressure) and preventive measures to reduce morbidity and mortality. There are no direct effective therapies available. Over the last fifteen years, pre-clinical studies in regenerative medicine utilizing cell-based therapy have generated enthusiasm as a possible treatment option for traumatic brain injury. In these studies, stem cells and progenitor cells were shown to migrate into the injured brain and proliferate, exerting protective effects through possible cell replacement, gene and protein transfer, and release of anti-inflammatory and growth factors. In this work, we reviewed the pathophysiological mechanisms of traumatic brain injury, the biological rationale for using stem cells and progenitor cells, and the results of clinical trials using cell-based therapy for traumatic brain injury. Although the benefits of cell-based therapy have been clearly demonstrated in pre-clinical studies, some questions remain regarding the biological mechanisms of repair and safety, dose, route and timing of cell delivery, which ultimately will determine its optimal clinical use.
Ischemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long‐term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow–derived mesenchymal stem/stromal cell (BM‐MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM‐MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM‐MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell‐based combination treatments.
Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge potential for application in the treatment of TBI. MSCs have immunosuppressive properties that reduce inflammation in injured tissue. As such, they could be used to modulate the secondary mechanisms of injury and halt the progression of the secondary insult in the brain after injury. Particularly, MSCs are capable of secreting growth factors that facilitate the regrowth of neurons in the brain. The relative abundance of harvest sources of MSCs also makes them particularly appealing. Recently, numerous studies have investigated the effects of infusion of MSCs into animal models of TBI. The results have shown significant improvement in the motor function of the damaged brain tissues. In this review, we summarize the recent advances in the application of MSCs in the treatment of TBI. The review starts with a brief introduction of the pathophysiology of TBI, followed by the biology of MSCs, and the application of MSCs in TBI treatment. The challenges associated with the application of MSCs in the treatment of TBI and strategies to address those challenges in the future have also been discussed.
Alzheimer’s disease, Parkinson’s disease, traumatic brain and spinal cord injury and neuroinflammatory multiple sclerosis are diverse disorders of the central nervous system. However, they are all characterized by various levels of inappropriate inflammatory/immune response along with tissue destruction. In the gastrointestinal system, inflammatory bowel disease (IBD) is also a consequence of tissue destruction resulting from an uncontrolled inflammation. Interestingly, there are many similarities in the immunopathomechanisms of these CNS disorders and the various forms of IBD. Since it is very hard or impossible to cure them by conventional manner, novel therapeutic approaches such as the use of mesenchymal stem cells, are needed. Mesenchymal stem cells have already been isolated from various tissues including the dental pulp and periodontal ligament. Such cells possess transdifferentiating capabilities for different tissue specific cells to serve as new building blocks for regeneration. But more importantly, they are also potent immunomodulators inhibiting proinflammatory processes and stimulating anti-inflammatory mechanisms. The present review was prepared to compare the immunopathomechanisms of the above mentioned neurodegenerative, neurotraumatic and neuroinflammatory diseases with IBD. Additionally, we considered the potential use of mesenchymal stem cells, especially those from dental origin to treat such disorders. We conceive that such efforts will yield considerable advance in treatment options for central and peripheral disorders related to inflammatory degeneration.
Traumatic brain injury is one of the leading causes of mortality and morbidity worldwide. At present there is no effective treatment. Previous studies have demonstrated that topical application of adipose tissue-derived mesenchymal stem cells can improve functional recovery in experimental traumatic brain injury. In this study, we evaluated whether hypoxic preconditioned mesenchymal stem cells could enhance the recovery from traumatic brain injury. Traumatic brain injury was induced with an electromagnetically controlled cortical impact device. Two million mesenchymal stem cells derived from the adipose tissue of transgenic green fluorescent protein Sprague-Dawley rats were cultured under either hypoxic (2.5% O2 for 18 hours) (N = 30) or normoxic (18% O2) (N = 30) conditions, then topically applied to the exposed cerebral cortex within 1 hour after traumatic brain injury. A thin layer of fibrin was used to fix the cells in position. No treatment was given to the animals with traumatic brain injury (N = 30). Animals that underwent craniectomy without traumatic brain injury were treated as the sham group (N = 15). Neurological functions were evaluated with water maze, Roto-rod and gait analysis. Animals were sacrificed at days 3, 7, and 14 for microscopic examinations and real-time polymerase chain reaction analysis. The rats treated with hypoxic mesenchymal stem cells showed the greatest improvement in neurological function recovery. More green fluorescent protein-positive cells were found in the injured brain parenchyma treated with hypoxic mesenchymal stem cells that co-expressed glial fibrillary acidic protein, Nestin, and NeuN. Moreover, there was early astrocytosis triggered by the infiltration of more glial fibrillary acidic protein-positive cells and microgliosis was suppressed with fewer ionized calcium binding adapter molecule 1-positive cells in the penumbra region of hypoxic mesenchymal stem cells group at day 3. Compared with normoxic mesenchymal stem cells and traumatic brain injury only groups, there was significantly (p < 0.05) less neuronal death in both the hippocampus and penumbral regions in sections treated with hypoxic mesenchymal stem cells as determined by Cresyl violet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining respectively. The expression of pro-inflammatory genes (interleukin 6, interleukin 1a, interleukin 1b, tumor necrosis factor α) was upregulated and apoptotic gene (Caspase-3) expression was suppressed at day 3. Anti-inflammatory (interleukin 10) and anti-apoptotic (BCL2 associated agonist of cell death) gene expression was upregulated at days 7 and 14. Our study showed that a hypoxic precondition enhanced the beneficial effects of mesenchymal stem cells on neurological recovery after traumatic brain injury.
Umbilical Cord Mesenchymal Stem Cells:
The New Gold Standard for Mesenchymal
Stem Cell-Based Therapies?
Introduction
Mesenchymal stromal cells (MSCs) are attractive
cells due to their capacity of long-term ex vivo proliferation, multilineage
differentiation potential, and immunomodulatory properties. These cells were first identified
and isolated from the bone marrow (BM) and have emerged
as powerful tools in tissue engineering and regeneration.1 Although adult
BM is the most common and best-characterized
source of MSCs, Wharton’s jelly (WJ) of the umbilical cord
provides a novel source of MSCs with higher accessibility
and fewer ethical constraints than BM holding great promise
as an alternative. WJ in an extra-embryonic tissue that is
easily obtained after birth, and it has initially been described
by Thomas Wharton in 1656.2 While the isolation of MSCs
from BM requires an invasive procedure for the donor,
MSCs can be noninvasively isolated from WJ.3 These WJMSCs are
believed to be more primitive than MSCs derived
from more mature tissue sources and to have intermediate
properties between embryonic and adult stem cells.4 Moreover,
WJ-MSCs are available in potentially large quantities,
have a fast proliferation rate, a great expansion capability,
do not induce teratomas, and harbor strong immunomodulatory capacities.5,6
In this review, we will focus on the similarities and differences between
WJ-MSCs and MSCs from other sources
with regard to their proliferation, their surface markers, and
their transcriptome profiles. The controversy between their
paracrine effects and trans-differentiation potential will be
discussed. In addition, we will particularly highlight their
roles as (a) immunomodulators and the mechanisms involved in their
immunosuppressive properties, as (b) antitumor agents, (c) migratory
curative cells with (d) a special
emphasis on their clinical and therapeutic applications in
autoimmune and neurodegenerative diseases.
Clinical-grade human umbilical cord-derived
mesenchymal stem cells reverse cognitive aging via
improving synaptic plasticity and endogenous
neurogenesis
Cognitive aging is a leading public health concern with the increasing aging population, but there is still lack of specific
interventions directed against it. Recent studies have shown that cognitive function is intimately affected by systemic milieu in
aging brain, and improvement of systemic environment in aging brain may be a promising approach for rejuvenating cognitive
aging. Here, we sought to study the intervention effects of clinical-grade human umbilical cord-derived mesenchymal stem cells
(hUC-MSCs) on cognitive aging in a murine model of aging. The conventional aging model in mice induced by D-galactose (D-gal)
was employed here. Mice received once every two weeks intraperitoneal administration of hUC-MSCs. After 3 months of
systematical regulation of hUC-MSCs, the hippocampal-dependent learning and memory ability was effectively improved in aged
mice, and the synaptic plasticity was remarkably enhanced in CA1 area of the aged hippocampus; moreover, the neurobiological
substrates that could impact on the function of hippocampal circuits were recovered in the aged hippocampus reflecting in:
dendritic spine density enhanced, neural sheath and cytoskeleton restored, and postsynaptic density area increased. In addition,
the activation of the endogenic neurogenesis which is beneficial to stabilize the neural network in hippocampus was observed
after hUC-MSCs transplantation. Furthermore, we demonstrated that beneficial effects of systematical regulation of hUC-MSCs
could be mediated by activation of mitogen-activated protein kinase (MAPK)-ERK-CREB signaling pathway in the aged
hippocampus. Our study provides the first evidence that hUC-MSCs, which have the capacity of systematically regulating the aging
brain, may be a potential intervention for cognitive aging.
Umbilical Cord Tissue-Derived Cells as Therapeutic Agents
1. Introduction
There is a plethora of papers covering the topic of stem cells
(SC) and their potential for use in regenerative medicine [1–
5]. To date various types of stem cells have been described in
humans from a variety of tissues, including preimplantation
embryos, foetuses, birth-associated tissues, and different
adult tissues [6]. Based on biochemical and genomic markers,
they can be broadly classified into embryonic stem cells
(ESC), mesenchymal stem cells (MSCs), and haematopoietic
stem cells (HPS). The so-called neonatal MSC sources,
including the placenta, amniotic fluid, and UC, have fewer
limitations than cells from other tissues. It has been shown
that the cells in these organs are more similar to early
embryonic cells, both in surface marker portrait and differentiation
potential. The UC is rich in cell material and is
the most homogeneous formation in comparison with other
provisional organs
Review Article
Umbilical Cord as Prospective Source for Mesenchymal Stem
Cell-Based Therapy
Mesenchymal Stem Cells from Human Umbilical Cord
Express Preferentially Secreted Factors Related to
Neuroprotection, Neurogenesis, and Angiogenesis
Abstract
Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and
strokes because of their ability to promote endogenous angiogenesis and neurogenesis via a variety of secreted
factors. MSCs found in the Wharton’s jelly of the human umbilical cord are easily obtained and are capable of
transplantation without rejection. We isolated MSCs from Wharton’s jelly and bone marrow (WJ-MSCs and BMMSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially
secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced
better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded
better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic
death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic
stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell
migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a
better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the
development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology
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