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.
Mesenchymal stem cells (MSCs) have been widely studied and increasingly recognized as a potential therapeutic with the ability to initiate and support tissue regeneration and remodeling. While over 1100 clinical trials have been conducted to assess the therapeutic benefits of MSCs, there continues to be widespread variation surrounding the potential treatment outcomes associated with these cells.
This review, authored by Chang, Yan, Yao, Zhang, Li, and Mao, focuses primarily on profiling the effects of the secretome, or the effects of paracrine signals of MSC, as well as highlights the various engineering approaches used to improve these MSC secretomes. Chang et al. also review recent advances in biomaterials-based therapeutic strategies for the delivery of MSCs and MSC-derived secretomes.
Recent research has demonstrated paracrine signaling as the primary mechanism of MSC therapeutic efficacy. This shift towards the MSC secretome in applications ranging from cartilage regeneration to cardiovascular and other microenvironments has demonstrated its therapeutic potential in prevalent injury models. Additionally, the versatility of MSCs allows them to be specifically tailored using biomaterials toward specific therapeutic outcomes.
A specific example of MSC secretome’s therapeutic potential is their ability to support cardiovascular tissue repair through minimization of fibrotic scarring of cardiac tissue typically observed to occur during a myocardial infarction (MI). Additionally, research has demonstrated MSC secretomes facilitate the proliferative, angiogenic, and anti-inflammatory phases of the wound healing process.
Secretome transfer occurring between MSCs and other cells in the target area primarily occurs through the release of extracellular vesicles (EVs) and is considered a safer form of therapeutic application compared to MSC therapy. MSC secretomes can also be specifically engineered through hypoxia, treatment with bioactive agents, and modulating cell-cell and ECM interactions in the MSC culture.
One of the biggest challenges facing the therapeutic efficacy of MSC is their limited cell survival, retention, and engraftment following injection or transplantation (found to be as low as 1% surviving one day after implantation). Recent studies have demonstrated MSC secretome, and specifically, EVs, although they remain a significant obstacle, are a promising alternative and able to bypass a number of cellular challenges, including cell survival.
Further consideration and approaches to increasing survival rates of MSCs include experimenting with a wide variety of biomaterials as a way to promote adaptation in the target implantation area. This includes looking for biomaterials to regulate oxygen tension levels, glucose supply, mechanical stress, and pH levels, which collectively can be used to regulate metabolic pathways of the MSC, effectively influencing cell survival and their ability to be used as therapeutic treatment options.
Despite the recent advances in the use of MSC secretomes and their delivery strategies, Chang et al. call for continued study of the subject and specifically recommend developing a specific set of paracrine cues to be used as a well-defined formulation in future therapeutic applications.
The authors also point out that the use of EVs and other direct applications of the MSC secretome are thought to be promising for the treatment of osteoarthritis, ischemic stroke, and coronavirus-related diseases. Considering this, Chang et al. highlight the increasing need to fully understand the paracrine signaling effects of MSC therapies and the delivery strategies associated with this application.
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that currently affects nearly 6 million people worldwide and is currently the second most common neurological condition, behind only Alzheimer’s.
Although the exact cause of PD remains unclear, the condition is characterized by the gradual loss of nerve cells in the brain responsible for producing the neurotransmitter dopamine. While no cure for PD currently exists, current therapeutic treatment approaches focus on improving quality of life but are not able to prevent or slow the progression of the disease.
Recent research has demonstrated positive effects of mesenchymal stem cell (MSC) transplantation that has been associated with secromes; noted beneficial effects include providing a self-regulated regenerative response that limits the area of lesions. Additionally, these MSC-derived secretomes compose soluble factors and encapsulated extravesicles (EV). These EVs have been found to have a significant impact on physiological processes, including cell-to-cell communication.
Considering MSCs are readily available and easily isolated from a number of sources, including adipose tissue, umbilical cord Wharton’s Jelly, bone marrow, and dental pulp, these stem cells are thought to hold potential as a therapeutic approach to managing PD.
As part of this review, d’Angelo et al. highlight a number of studies demonstrating the potential of MSCs in improving a number of conditions and symptoms consistent with those demonstrated in PD. In these studies, animal models demonstrate improved motor behaviors and correction of functional impairment after transplantation of MSCs.
The authors point out that further research exploring cell-free, therapeutic, personalized approaches for the different neurodegenerative diseases, including PD, is needed.
d’Angelo et al. also note that, while MSC-derived secretomes have shown positive effects on neuronal cell survival, differentiation, and proliferation, further studies are needed to fully understand all of the bioactive molecules.
Since MSC-derived secretomes are able to stimulate neurotrophic and neuronal survival pathways and appear to counteract neuronal death, they could potentially be a beneficial tool in future management and prevention efforts for a number of neurodegenerative conditions, including Parkinson’s disease, Alzheimer’s disease, and stroke.
Promising early research shows that when introduced into a brain injured by stroke, extracellular vesicles (EVs), also known as exosomes, a bioactive substance secreted by mesenchymal stem cells, have been associated with improved blood vessels creation, increased formation of neurons, and enhanced preservation of the neurological structure; these findings demonstrate a promising stem cell-derived stroke therapy that serves as an alternative approach to current stem cell infusion treatment options.
With nearly 14 million people suffering strokes each year, strokes continue to be the leading cause of physical disability among adults; between 25 percent and 50 percent of stroke survivors are left with significant and debilitating disabilities.
Because mesenchymal stem cells, or MSCs, secrete extracellular vesicles thought to reduce inflammation, enhance autophagy, and promote regeneration of damaged cells, researchers evaluating potential regenerative strategies for stroke-induced neurologic deficits have identified these MSC-derived EVs as a viable option for stroke therapy.
Although the reported beneficial effects of EV therapy has been observed in studies completed on animals, there is an increasing number of clinical studies currently being conducted on humans that suggest MSC EV stem cell therapy is a potentially safe and effective therapeutic option to improve outcomes in several various human applications.
Specifically, this EV-mediated therapy appears to offer an off-the-shelf treatment option that is potentially effective in crossing the blood-brain-barrier (BBB) while also avoiding cell-related problems, including the formation of tumors and infarcts resulting from vascular occlusions, or blood clots, consistent with those observed in acute ischemic stroke.
While there appears to be a promising upside to MSC EV therapy for the treatment of stroke, studies are on-going to discover the optimal therapeutic treatment of stroke patients. Some areas to continue researching are the optimal time and best mode of application of EVs in stroke patients (most stroke-related recovery occurs in the first few months following the stroke).
As research continues into the effectiveness of MSC-EV therapy for stroke, early indications are that EVs derived from mesenchymal stem cells could be a viable cell-free treatment option for patients recovering from a severe stroke.
Osteoarthritis is a disease in which joint cartilage degenerates and the bony edges of the joint rub against each other. The disease causes pain and disability in the affected joint. There is no cure for osteoarthritis, except perhaps for artificial joint replacement surgery. Patients who are not candidates for surgery must get by with pain medications, braces, and physical therapy.
Given that osteoarthritis affects millions of people and there are limited options for long-term treatments other than major surgery, researchers are working very hard to find additional ways to manage this condition. One of the most exciting developments has been in the field of regenerative medicine, also known as stem cell therapy.
Stem cells injected into arthritic knees, for example, may help reduce the patient’s pain, protect cartilage, or even slightly heal the joint damage. Many patients feel relief and see improvements from just one therapy. Some with more advanced conditions may require a more maintenance plan. But today, researchers are now focused on the mesenchymal stem cell secretome.
What is a mesenchymal stem cell secretome? A mesenchymal stem cell secretome is the total of all of the molecules that mesenchymal stem cells secrete or release to support, restore, and regenerate tissue. The molecules released from mesenchymal stem cells, mostly through stem cell exosomes, exert many powerful benefits on joints.
From laboratory experiments in animals, we know the mesenchymal stem cell secretome is anti-apoptotic, which means it protects joint cells from committing programmed cell suicide. The secretome is also anti-fibrotic, and fibrosis can be damaging to joints and make them stiff. The secretome is pro-chondrogenic and pro-angiogenic, which means it helps build cartilage and blood vessels, respectively.
Lastly, the mesenchymal stem cell secretome modulates the immune system. While rheumatoid arthritis is considered the major inflammatory joint disease, inflammation also takes place in osteoarthritis. So, the mesenchymal stem cell secretome can modulate the immune system and reduce joint inflammation.
The main way that patients can reap the potential benefit of the mesenchymal stem cell secretome is through exosomes. Exosomes are small particles that contain most of the substances released in the secretome. Exosome treatment does not require stem cell infusions, and many, many more exosomes can be administered during a treatment session than stem cells, mainly because they are physically much smaller.
The concept of mesenchymal stem cell secretome is rather new, but it is a powerful concept in the treatment of osteoarthritis. As more human clinical studies are done, we should be able to unlock the power of the secretome for patients with osteoarthritis.
Reference: Mancuso P, Raman S, Glynn A, Barry F, Murphy JM. Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome. Front Bioeng Biotechnol. 2019;7:9. Published 2019 Jan 29. doi:10.3389/fbioe.2019.00009
Over the past decade, scientists have learned that the molecules that mesenchymal stem cells release are every bit as important to regenerative medicine as the stem cells themselves. Stem cells release exosomes, which are tiny packets that contain countless molecules of microRNA, cytokines, and growth factors. These molecules are mainly what allows stem cells to help the body regrow and repair.
Dr. Vizoso and colleagues published a review article that describes the many benefits of the secretome, that is, stem cell exosomes and the substances they produce. They not only explain why exosomes are helpful in regenerative medicine but why stem cell exosomes bring a powerful enhancement to stem cells themselves.
Compared to exosomes, whole stem cells are rather big—one can safely inject far more exosomes than stem cells in each treatment. And, really, it seems that the stem cell exosomes are what is supplying most of the benefits.
Stem cells can be made to produce millions of exosomes. These stem cell exosomes can then be collected, stored, shipped, and infused with much less cost and aggravation than stem cells themselves. Exosomes have small molecules on their surfaces that allow them to seek out and find areas in the body where they are needed. Stem cells often need to be injected near the site of injury. Exosomes may work if simply infused into a vein.
Dr. Vizoso and coauthors make a persuasively strong argument about the potential benefits of infusing stem cell exosomes instead of stem cells themselves. They also point out the potential limitations of the process, given the current technology. For example, stem cells would need to be made “immortal” so that they can keep producing large amounts of the same sorts of exosomes over time. Fortunately, the techniques of cell immortalization have been around for at least 30 years. Thus, most of the barriers to widespread, large scale exosome use are things scientists already know how to overcome.
While there may still be benefits for direct stem cell infusions, the future of research is moving forward with stem cells and exosomes.
Reference: Vizoso, F., et al. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. International Journal of Molecular Sciences. 2017, 18(9), 1852.
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