Currently, it’s estimated that nearly 1.5 million Americans are living with type 1 diabetes (T1D), a number that is expected to increase to over 2 million by the year 2040[1]. In the U.S. alone, healthcare costs and lost wages directly related to T1D currently exceed $16 billion per year.
While the most common treatment for T1D continues to be regular injections of insulin and is effective in improving hyperglycemia, the treatment has proven ineffective in removing autoimmunity and regenerating lost islets. Additionally, islet transplantation, a recent and experimental treatment option for T1D, has demonstrated its own set of issues, primarily poor immunosuppression and a limited supply of human islets.
The rapid progression and recent advances in stem cell therapy, including mesenchymal stem cell (MSC) therapy, have created interest in using stem cells to help manage the symptoms of T1D. In this review, Hai Wu reviewed the properties of MSCs and highlighted the progress of using MSCs in the potential treatment of T1D.
Diabetes clinics have demonstrated progress using depleting antibodies as a way to treat T1D, but continue to find remission to typically last for only a short period of time. Additionally, treatment with these antibodies has shown not to discriminate between different types of T cells, meaning even T cells involved in maintaining normal immune function are depleted; this phenomenon has been shown to contribute to other serious health complications.
In addition to the immunomodulatory effects demonstrated by MSCs, they have also shown the ability to recruit and increase the immunosuppressive cells of host immunity. Recent results from clinical trials have shown that just a single treatment with MSCs provided a lasting reversal of autoimmunity and improved glycemic control in subjects with T1D.
While these results demonstrate the potential of MSCs for a wide range of autoimmune diseases, Wu points out that the small sample size of these studies necessitates further clinical trials before considering approval for use in clinical applications.
Studies of human islets and human islet transplantation have been limited because of a shortage of pancreas donors. Although unable to be definitively demonstrated, and considering their ability to differentiate into other cell types, there is a hypothesis that MSCs can transdifferentiate to insulin-producing cells. While not yet fully understood, this hypothesis is further supported by the observation of crosstalk between MSCs and the pancreas in diabetic animals.
Other in vivo studies examining this relationship has produced mixed results. For example, Chen et al. (2004) were unsuccessful in attempts to transdifferentiate MSCs into insulin-producing cells in vitro. On the other hand, several studies, including those by Timper et al. (2006) and Chao et al. (2008) demonstrate the formation of islet-like clusters from in vitro cultured MSCs and the possibility of using MSCs as a source of human islets in vitro.
Despite these promising findings, the author highlights that most of these studies failed to generate sufficient amounts of islets required for human transplantation and long-term stability. However, Wu notes recent advances in tissue engineering, including biocompatible scaffolds, might better support in vitro generation of islets from MSCs.
The author concludes that MSCs can be isolated from multiple tissues, are easily expanded and genetically modified in vitro, and are well-tolerated in both animal and human studies – making them a good candidate for future cell therapy. On the other hand, stem cell therapy alone might not be enough to reverse the autoimmunity of T1D, and co-administration of immunosuppressive drugs may be necessary to prevent autoimmunity.
MSCs have shown great promise in the field of regenerative medicine. While stem cells used as a potential treatment for T1D appear generally safe, the author calls for future in-depth mechanistic studies to overcome the identified scientific and manufacturing hurdles and to better learn how cell therapy can be used to treat – and eventually cure – T1D.
Mesenchymal stem cells (MSCs) have demonstrated the ability to differentiate into a number of different cells; they also demonstrate immunomodulatory properties that have great potential for use as a stem cell-based therapeutic treatment option and for the treatment of autoimmune diseases – including rheumatoid arthritis (RA).
RA is a chronic and debilitating inflammatory disorder that not only affects the joints, muscles, and tendons, but also damages a number of other body systems, including the eyes, skin, lungs, heart, and blood vessels[1]. It is estimated that roughly 1.5 million Americans are afflicted by RA. While the exact cause of RA is not yet fully understood, the condition is one of over 80 known autoimmune diseases occurring as a result of the immune system mistakenly attacking the body’s own healthy tissue.
Current treatment of RA primarily involves the use of steroids and antirheumatic drugs used primarily to manage associated symptoms of the condition, rather than treat the condition itself. These drugs are also commonly associated with a number of unwanted side effects with users often developing resistance to the medication after prolonged use.
Considering the relative ineffectiveness of drugs designed to treat RA and RA-associated symptoms, scientists have turned to investigate the use of MSC-based therapy as a potential treatment for RA.
As part of this investigation, Sarsenova et al. examined both conventional and modern RA treatment approaches, including MSC-based therapy, by examining the connection between these stem cells and the innate and adaptive immune systems. This review also evaluates recent preclinical and clinical approaches to enhancing the immunoregulatory properties of MSCs.
Through a number of in vitro studies, researchers have realized that MSCs have the ability to inhibit the proliferation of effector memory T cells which, in turn, prevents the proliferation of inflammatory cytokine production. Additionally, these studies have also demonstrated that MSCs are able to modulate functions of the innate immune system by inducting the inflammatory process and activating the adaptive immune system.
Preclinical studies have demonstrated the ability of MSCs to suppress inflammation both through interactions with cells of the immune system and through paracrine mechanisms. This has been demonstrated to be very important as cells of the innate immune system have been shown to have an important role in both the development and progression of RA.
While a number of clinical studies evaluating the effectiveness of MSC-based therapies for the treatment of RA were still ongoing at the time of publication, the nine completed studies primarily demonstrated that using MSCs for the treatment of RA is safe, well tolerated in both the short and long-term, and provides clinical improvements in RA patients.
Despite the many positive and promising outcomes observed through these clinical trials, the authors of this review also point out some limitations associated with the treatment of RA with MSCs. These limitations include many of the referenced studies lacking a placebo control, low enrollment in some studies, and a lack of optimal protocol (for both MSC sourcing and route of administration) for RA treatment with MSCs.
Considering these limitations, Sarsenova et al. point out the need for more well-defined and effective therapeutic windows for the treatment of RA with MSCs, including MSC priming to promote an anti-inflammatory phenotype, in a future study as a way to better understand the perceived benefits of a stem-cell therapy for the treatment of RA and other autoimmune diseases.
The number of people experiencing autoimmune diseases (ADs) continues to increase worldwide. Currently, it’s estimated that between 2 and 5% of the global population is afflicted with the most severe forms of these diseases, including type 1 diabetes (T1DM), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA).
An autoimmune disease can occur nearly anywhere in the body and is the result of the immune system mistakenly attacking your body instead of protecting it. While the reason this occurs is not yet fully understood, there are over 100 different types of autoimmune diseases classified into two types: organ-specific (T1DM) and multiple system-involved conditions (SLE and RA).
In addition to T1DM, SLE, and RA, other common autoimmune conditions include Crohn’s disease, ulcerative colitis, psoriasis, inflammatory bowel disease (IBS), and multiple sclerosis (MS).
In addition to not fully understanding why these conditions occur, conventional treatments (mainly in the form of immunosuppressants) alleviate associated symptoms but do not provide lasting or effective therapy for preventing or curing these diseases.
In recent years, mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EV) have demonstrated immunosuppressive and regenerative effects, and are now being investigated as promising new therapies for the treatment of ADs. In this review, Martinez-Arroyo et al. provide a complete analysis of current MSC and MSC-EV efforts in regard to some of the most severe ADs (T1DM, RA, and SLE) as a way to demonstrate progress in the discovery and application of new stem cell therapies for the treatment of ADs.
Initial research by the International Society of Cellular Therapy in 2006 established that MSCs are able to exert a range of biological functions, with the most well-known being immunosuppressive and regenerative effects, suggesting that MSCs-based therapies for the treatment of ADs is possible. Additional research has also demonstrated MSCs role in regenerative medicine to be safe and effective in treating a wide variety of diseases and injuries.
Further study has demonstrated that MSCs influence immune cell proliferation, differentiation, and function. While this is promising, research also suggested that the microenvironment influences the induction, increase, and maintenance of MSCs immunoregulatory role.
Considering this, the authors of this review suggest that blocking immune cell reprogramming while maintaining MSC roles in the immune microenvironment would provide new insights into identifying strategies for the biological treatment of ADs.
Current research and findings also support the use of MSC for the regeneration of tissue. This same research has also raised concerns related to cell survival, genetic instability, loss of function, and immune-mediated rejection. Because of this, Martinez-Arroyo et al. call for further study to better understand the biology, biomaterials, and tissue engineering used during MSC therapy.
The authors conclude this review by pointing out that there has been a revolutionary change in perspective in the field of MSC-based therapies for the treatment of AD primarily stemming from the use of MSC-EVs as potential therapeutic options.
Additionally, when comparing the use of MSCs to MSC-EVs, the authors highlight several advantages demonstrated by MSC-EVs. These advantages include providing stability and safety, avoiding tumorigenesis, genetic mutability, and immunogenicity when compared to MSCs, and allowing for several modifications to their surface and cargo – all enhancing their potential as viable treatment options for ADs.
While MSC-EVs demonstrate tremendous potential, the authors call attention to the fact that the use of MSC-EVs is still in the initial research and development phases and faces major obstacles and limitations in a number of areas, including overcoming the optimization of methods for MSC-EV characterization, high-scale production, and purification and improving MSC-EV targeting.
Considering these limitations, Martinez-Arroyo calls for further research with animal models and clinical assays as a way to test the safety and efficiency of using MSC-EVS as cell-free therapy for ADs.
Spinal cord injury (SCI) continues to be a significant cause of disability. In fact, it is estimated that annual SCIs account for nearly 18,000 injuries in the United States and between 250,000 and 500,000 injuries worldwide[1]. While the main cause of SCIs in the United States continues to be motor vehicle accidents, other contributors include falls, recreational accidents, and complications from medical procedures.
In their attempt to minimize damage after SCI, researchers have proposed several treatment options. This review conducted by Zoehler and Rebellato identifies cell therapy, and specifically treatment with mesenchymal stem cells (MSCs), as the primary form of neuroregenerative treatment for SCIs.
Research has shown that mammals are unable to regenerate nervous cell tissue in an area damaged as a result of a SCI, which means currently they will be subject to permanent disability after suffering such an injury.
Current treatments for SCIs have proven unable to repair the damage, rather they are used to relieve SCI-associated symptoms, including pressure and scarring, while also attempting to reduce hypoxia resulting from edema and hemorrhaging. One such treatment, spinal compression surgery, has shown to be successful at achieving these outcomes with results being much better if the surgery is completed within 24-hours of the SCI.
Another treatment currently used after SCI is methylprednisolone sodium succinate (MPSS) administered intravenously. In addition to inhibiting lipid peroxidation, MPSS inhibits post-traumatic spinal cord ischemia, supports aerobic energy metabolism, and attenuates neurofilament loss. However, because this treatment is associated with gastrointestinal bleeding and infection, it is recommended to be used with caution.
While not yet fully understood, cell therapy – and specifically therapy using MSCs – has presented promising findings related to regenerating tissue after a SCI. It is widely believed that MSCs effectiveness is related to their ability to secrete different factors and biomolecules.
MSCs also reduce inflammation, which is important in this application because inflammation is known to be a secondary event after sustaining initial SCI.
The authors point out that a better understanding of the specific mechanisms related to the regenerative effects of MSCs used when treating SCI is required in order to develop future MSC-based treatments designed to address SCI in humans. Currently, despite the recent increased focus on the use of cell therapy to treat SCI and central nervous system trauma, there is no consensus on a number of essential topics, including cell type, source, number of cells infusion pathways, and number of infusions to achieve this goal.
Zoehler and Rebellato also point out that it’s important to better understand how the reorganization of injured neural tissues associated with MSCS is related to the restoration of neural function.
Numerous animal model and human clinical trials have confirmed the regenerative and neuroprotective potential of MSCs without adverse effects during or after infusion. The authors close this review by highlighting that MSCs continue to demonstrate potential as an alternative for SCI therapy, primarily because the therapy is not limited by the time of injury and has shown measurable improvements in patients with complete and incomplete SCI.
Source: Fracaro L, Zoehler B, Rebelatto CLK. Mesenchymal stromal cells as a choice for spinal cord injury treatment. Neuroimmunol Neuroinflammation 2020;7:1-12. http://dx.doi.org/10.20517/2347-8659.2019.009
Stem cells, and specifically mesenchymal stem cells (MSCs), have long been considered as a promising therapeutic agent for the treatment of a wide variety of degenerative and ischemic diseases. Over this time, MSC immunomodulation, their capacity for multilineage differentiation, and their ability to self-renew have been well established and are now considered to be clinically relevant.
Considering this, scientists have hypothesized that the therapeutic application of MSCs in immune/inflammatory contexts may be more efficacious than other, more traditional approaches currently used in the field of regenerative medicine.
In this review, Wang et al. specifically focus on the non-traditional use of MSCs as a potential treatment towards immune/inflammatory-mediated diseases and identify important findings and trends in this area of study as they relate to specific immune/inflammation-mediated diseases, including graft-versus-host disease (GVHD), multiple sclerosis (MS), joint diseases [including Osteoarthritis (OA) and rheumatoid arthritis (RA)], inflammatory bowel disease (IBD), and inflammatory airway and pulmonary diseases.
While there have been several promising results indicated in a number of trials using MSC for treatment of GVHD, the same results have not consistently been observed in all trials. One potential reason for the observed difference in results could potentially be a result of heterogeneity observed in conducted trials. Significant observed differences included those between pediatric and adult patients, the type of stem cell transplanted, as well as the MSCs utilized. Interestingly, there has also been a significant difference between results of published trials occurring in Europe (generally positive) compared to those trials occurring in North America (more equivocal results). While MSCs have strong potential for use as a therapeutic agent for GVHD, additional study into patient population and stringent MSC processing criteria are required before consistent and reproducible results are able to be delivered.
As of the publication of this review (2016), Wang et al. identified 23 registered clinical trials using MSCs for the treatment of MS. Additionally, animal models exploring the use of MSCs for the treatment of MS have demonstrated strong therapeutic effects. While many of the clinical trials using MSCs for the treatment of MS were ongoing, several animal models and many additional preclinical studies demonstrated MSCs to have therapeutic efficacy for the treatment of patients with MS.
Since cartilage cannot regenerate, the use of MSCs in treatment of joint diseases are considered a strong therapeutic option for several of these conditions, including OA and RA. Considering that prevention of inflammation and immune attacks on joints must occur in order for the joint repair to occur, and considering the immunosuppressive properties associated with MSCs, MSCs are thought to be well suited for use in the treatment of OA – a thought that has been well supported in both small and large animal studies.
Additionally, several of the 38 clinical trials underway at publication of this review indicated positive results in reduction of OA-induced pain and other related symptoms and for joint repair as observed by cartilage regeneration. On the other hand, similar results have not been observed for RA. The authors point to the detailed mechanistic differences between RA and OA as the likely reason for the observed therapeutic differences observed between the two joint diseases.
The 19 clinical trials and several animal model studies have overwhelmingly demonstrated that MSC therapy is both safe and a highly viable therapeutic option for the treatment of IBD, especially CD fistula formations.
Considering that between 80-90% of MSCs delivered intravenously have been observed to rapidly reach the lungs, MSC therapy has been thought to be particularly well suited for treatment in several pulmonary diseases, including COPD, asthma,emphysema, and even pneumonia. However, while animal models and preclinical studies have demonstrated MSCs to be safe in this application, the 29 registered clinical studies using MSCs for pulmonary disorders have also indicated the application to be safe – but have yet to replicate the efficacy observed and reported in the previously mentioned preclinical animal studies.
The authors of the review conclude that hundreds of clinical trials evaluating the effectiveness of MSC therapy in this application have demonstrated their use to be safe. However, the overwhelmingly positive results reported in preclinical animal studies have not yet been observed through these clinical trials. Considering these findings, Wang et al. call for a better understanding on both the mechanistic properties of MSC Immunomodulation and the pathophysiological details and subsets with specific disease entities as a way to better tailor MSC therapy.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that causes your immune system to mistakenly attack its own tissue and specifically affects the lining of the joints, resulting in painful swelling, bone erosion, and eventually permanent joint deformity.
With an estimated 1.5 million people in the U.S. living with RA, the disease affects nearly three times as many women as men. In addition to affecting the synovial joints and causing articular destruction and functional disability, an estimated 40% of those diagnosed with RA experience additional signs and symptoms that do not involve the joints; these affected areas often include most body systems and specifically the skin, eyes, lungs, nerves, heart, and blood vessels.
Multiple studies have demonstrated that bone marrow mesenchymal stem cells could be effective for treating a number of autoimmune diseases, including RA. However, little is known about the effectiveness of umbilical cord (UC)-MSCs as they relate to the treatment of autoimmune diseases, specifically RA.
Considering this, it comes as little surprise to learn that bone marrow MSCs (BM-MSCs) have been the most common source of MSCs used in the study of immunosuppression of autoimmune conditions. However, the collection of BM-MSCs requires aspiration, which is an invasive procedure. Additionally, the number of BM-MSCs and the differentiating potential of BM-MSCs both decrease significantly with age.
UC-MSCs, on the other hand, are collected using non-invasive procedures after birth and before the umbilical cord is discarded. Additionally, UC-MSCs have been well documented to possess properties of self-renewal and multipotent differentiation, making them a potential candidate for alternative sources of stem cells.
In this study, Liu et al. examined the suppressive effects of UC-MCSs on the proliferation, invasive behavior, and inflammatory responses of fibroblast-like synoviocytes (FLSs) from patients with RA.
At the conclusion of this study, the authors offered a number of key findings about the effectiveness of UC-MSCs in this application, including:
US-MSCs inhibited proliferation of FLSs from RA patients
US-MSCs suppressed the invasive behavior and MMP expression of FLSs from RA patients
US-MSCs suppressed the inflammatory response of FLSs from RA patients
UC-MSCs induced hyporesponsiveness of T lymphocytes from RA patients
UC-MSCs induced Tregs from RA patients
UC-MSCs prevented tissue damage and reduced inflammatory responses in CIA
The authors conclude by indicating the evidence provided by this study indicates that UC-MSCS can exert a profound inhibitory effect on FLSs and T cells from RA patients and that they might be a therapeutic perspective in RA. Source: “Therapeutic potential of human umbilical cord mesenchymal stem ….” https://pubmed.ncbi.nlm.nih.gov/21080925/.
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