Mesenchymal stem/stromal cells (MSCs) continue to be viewed as a source of cell therapy applications due to their immunomodulatory and anti-inflammatory effects and because of their ability to stimulate angiogenesis. In MSCs, these benefits are mainly attributed to the secretion of factors.
Despite MSCs’ known and favorable proliferation levels, multipotency, and immune response regulation, there are other important variables that should be considered when developing cell therapy applications, including the source of MSCs.
Considering that MSCs collected from different tissues can form heterogeneous cellular populations and manifest tissue-specific functional differences, the source of MSCs should be of primary consideration when developing new therapeutic approaches.
In this review, Paladino et al. present a review of recent research related to the therapeutic application of Wharton’s jelly MSC (WJ-MSC) harvested from umbilical cords and how these cells affect immune responses in comparison with other sources of MSCs.
Bone marrow-derived stem cells BM-MSCs have long been considered the favored source of MSCs and are the most used source of MSCs in clinical research. However, BM-MSCs have a history of showing mixed results and are not always recommended for use due to the invasive and painful process used to obtain the MSCs.
While other alternative sources, including adipose tissue, dental pulp, and menstrual blood, are available, WJ-MSCs are considered an easily accessible source of MSCs that are comparable to BM-MSC and have suffered less environmental interference and demonstrate higher proliferative capacity than other sources.
Studies using WJ-MSC in this capacity have shown their robust immunomodulatory potential. Specifically, the authors of this review reference a number of studies using various sources of MSCs, including WJ-MSCs that demonstrate immunomodulatory potential similar to other MSC sources. Studies also demonstrate that WJ-MSC is a better suppressor of specific inflammatory factors, including mixed lymphocyte reaction, and possesses higher levels of IL-17A (a key mediator in the treatment of graft-versus-host disease) than MSCs collected from other sources.
Paladino et al. conclude that the available literature indicates that WJ-MSCs possess immunological features comparable to MSCs from other sources, including bone marrow-derived MSCs. The authors also call for further study to identify the best therapeutic indications for WJ-MSCs as a substitute for other sources of MSC, including BM-MSC.
Liver disease accounts for nearly two million deaths annually and is responsible for 4% of all deaths (1 out of every 25 deaths worldwide); approximately two-thirds of all liver-related deaths occur in men.
Most forms of chronic liver disease result from viral infections, alcohol abuse, or metabolic disorders and eventually result in cirrhosis and liver failure. The only effective treatment for end-stage cirrhosis is liver transplantation. Unfortunately, considering organ shortages and the high cost associated with this type of medical procedure, liver transplants are not available in many countries.
As part of this review, Kang et al. discuss the therapeutic effects of MSCs in liver diseases to address questions regarding their efficacy and safety, evaluate recent advances in this area, and consider the potential risks and challenges in the use of MSC-based therapies for liver disease.
When considering the therapeutic effects of MSC therapy in chronic liver disease, the authors conclude that this treatment has shown to be effective, primarily due to their immunomodulation, differentiation, and antifibrotic properties exhibited by MSCs. The authors also point out that although the safety and therapeutic effects of MSC therapy have been observed in several clinical studies, to date the therapy has demonstrated only modest improvements in treating liver disease. Kang et al. attribute this modest improvement, in part, to the current limited feasibility of transplanted cells.
The authors provide a detailed review of the strategies that have been utilized to improve the effects of MSC transplantation, including tissue engineering, preconditioning, genetic engineering, and using extracellular vesicles as cell-free therapy, and summarize the future potential of each of these as ways to improve MSC transplantation.
Kang et al. also highlight several problems that must be considered and addressed before MSCs are fully accepted as clinical therapeutic treatment options for chronic liver disease; these problems include the potential for carcinogenesis and viral transmission. For example, previous animal studies have demonstrated a relationship between the development of sarcoma and the number of passages. While this has not been directly observed in clinical trials involving human MSCs, the follow-up period was too short to allow for observed evidence of this development. As a result, the authors call for a detailed study into the chromosomal integrity before MSC transplantation to ensure the safety of the procedure.
In addition to the potential for tumor cell growth, allotransplantation of MSC cells may involve the risk of viral transmission to the patients. As a result, the authors indicate that both MSC recipients and donors may need to be screened for the presence of specific viruses, including parvovirus B19, herpes simplex virus, and cytomegalovirus.
The authors conclude that the prospects of MSC-based cell therapy for treating chronic liver disease will be determined by standardizing the cell source, culture conditions, administration route, and the outcomes of future large-scale clinical trials.
Multiple sclerosis (MS) is a progressive auto-immune disease that affects the central nervous system (CNS). Currently, it is estimated that nearly 2 million people worldwide are affected by MS.
Characterized by the body attacking the myelin (the protective sheath that covers the nerve fibers), MS causes communication issues between the brain and the rest of the body. As the nerves continue to deteriorate, the condition can cause permanent damage.
Currently, there is no pharmaceutical treatment for MS, only medications that treat the symptoms of the condition.
In the field of regenerative medicine, mesenchymal stem cells (MSCs) have emerged as a candidate that could potentially treat a number of diseases, including MS. Specifically, MSCs have anti-inflammatory effects and have demonstrated the ability to differentiate in order to target the overactivity and self-antigen attacks observed in the development and progression of MS.
As part of this review, Alanazi et al. reviewed a number of clinical trials that have utilized MSCs isolated from a variety of sources, including peripheral blood, bone marrow (BM-MSCs), adipose tissue (AD-MSCs), umbilical cord (UCMSCs), and the placenta, in order to better understand their potential as a treatment option for MS.
An analysis of these clinical trials led the authors of this review to the consensus that MSCs appear effective in inhibiting CD4+ and CD8+ T cell activation, T regulatory cells, and macrophage switch into the auto-immune phenotype.
Further analysis of the specific MSCs used to treat MS by Alanazi et al. indicates that while BM-MSCs, AD-MSCs, and UCMSCs all demonstrate beneficial effects when applied to the treatment of MS, UCMSCs appear to be the best option.
According to the authors, UCMSCs demonstrate faster self-renewal than other MSCs, are able to differentiate into three germ layers, and can accumulate in damaged tissue or inflamed areas. Additionally, UCMSCs are also among the easiest MSCs to source, demonstrate a high concentration of MSCs, are safe and inexpensive, and are not associated with ethical issues.
Based on the information reviewed, Alanazi et al. recommend emphasizing the clinical utility of UCMSCs for regenerative medicine and immunotherapy, including for the treatment of MS.
Cigarette smoking continues to be the leading contributor to preventable disease and death in the United States, including cancer, heart disease, stroke, lung diseases, diabetes, and chronic obstructive pulmonary disease (COPD). Smoking cigarettes also increases the risk of tuberculosis, certain eye diseases, and problems of the immune system, including rheumatoid arthritis.
An abundance of clinical research has clearly shown the detrimental effects cigarette smoke has on nearly every area of the body. However, while assumed to be equally dangerous in its effect on stem cells, there is surprisingly little research exploring the negative implications of cigarette smoking on stem cells.
In this review, Nguyen et al. share findings of recent studies on the effects of cigarette smoking and nicotine on mesenchymal stem cells (MSCs), with a specific focus on dental stem cells.
With their ability to self-renew, develop into specialized cell types, and migrate to potential sites of injury, stem cells have demonstrated the potential to build every tissue in the body and have also demonstrated great potential for tissue regeneration and associated therapeutic uses.
As the potential benefits and weaknesses of stem cells continue to be discovered, researchers have found that cigarette smoking negatively impacts the abilities of stem cells while also limiting stem cell viability for transplantation and regeneration.
While there has been a recent decline in the percentage of U.S. adults who smoke, over 34 million U.S. adults continue to be regular cigarette smokers. Interestingly, research has demonstrated the concentration of nicotine to be significantly higher in saliva than in blood plasma following nicotine administration via cigarette, e-cigarette, and nicotine patch – in some cases measuring up to eight times higher concentrations. Considering this research and considering the established detrimental effects of e-cigarette vapor – and presumably nicotine – on teeth and dental implants, the authors of this review hypothesized that there would be a similar effect when dental stem cells are exposed to cigarette smoke.
Nguyen et al. reviewed research that determined cigarette smoke produced a negative impact on the proliferation and differentiation of dental pulp stem cells (DPSCs). Specifically, this research demonstrated a significantly higher depression of alkaline phosphatase (ALP) and osteocalcin (OC) genes in smokers when compared to nonsmokers. Additional studies found that smokers demonstrated reduced calcium deposition levels and production of ALP when compared to nonsmokers.
Cigarette smoke and nicotine were also found to negatively affect the migration capability of dental stem cells, slowing the migration rate by up to 12% in smokers while also producing a smaller reduction of scratch wound areas when compared to nonsmokers.
While there are not many studies directly comparing the effects of cigarette smoke and nicotine on MSCs and dental stem cells, the authors conclude that dental stem cells exhibit similar characteristics to bone marrow MSCs and that both of these types of stem cells demonstrate similar negative responses upon their exposure to nicotine.
While the authors call for further research to better understand the specific effects of cigarette smoke on dental stem cells, the authors conclude that the findings demonstrating similar responses to cigarette smoke and nicotine between dental stem cells and MSCs can be used to inform future dental stem cell studies. These findings will help dentists better identify which patients might be at an increased risk of poor healing in the oral cavity and if smoking cessation should be considered before undergoing any invasive or traumatic dental procedure, such as tooth extraction.
With nearly 15 million people affected worldwide each year, stroke continues to be the most prevalent cerebrovascular disease. Responsible for over 5 million deaths and another 5 million individuals suffering long-term disabilities, stroke also is the leading cause of mortality and morbidity worldwide.
Although there have been significant advances in both pharmacological and surgical therapies designed to treat the effects of stroke, effective therapy remains limited and primarily focused on managing the symptoms associated with a stroke rather than treating the causing factors or preventing the stroke at the onset.
Recently regenerative medicine, also known as stem cell therapy, and specifically mesenchymal stem cell (MSC)-based therapy has been identified as a potentially effective strategy for a wide range of diseases and health conditions, including stroke.
In this review, Li et al. examine current preclinical and clinical data from trials using MSCs in the treatment of stroke, the mechanisms underlying MSC-based therapy for stroke, and the challenges associated with the timing and delivery of MSCs.
Initial preclinical studies of the application of MSCs in the treatment of stroke demonstrated that transplantation of MSCs following ischemic stroke promoted improvement of cerebral function protected the ischemic neurons, and repaired brain damage. However, these studies were conducted in young and healthy subjects and failed to factor in the presence of comorbidities, such as diabetes and hypertension, more commonly observed in ischemic stroke patients.
Considering that 75% of strokes occur in the elderly and/or those with the previously mentioned comorbidities, the authors of this review focused their review on studies that incorporated these two factors into their trials.
While these preclinical studies of MSC-based therapy for stroke demonstrated promising results, including improved blood-brain barrier integrity, increased white matter remodeling, and improved neural repair, the authors point out that there has been a limited number of preclinical studies conducted and call for additional preclinical studies specifically utilizing the comorbidity model.
Although treatment of stroke using MSCs has been established to be safe and feasible in phase I and II clinical trials, there have been mixed findings as to the therapy’s efficacy. As a result of these varied findings, the overall efficacy in the treatment of ischemic stroke remains controversial. The authors consider several reasons for the inconsistency of results observed in these trials, including the varied number of patients, doses, and type of cell delivery, the timing of the cell therapy, and the treatment modalities used in these trials; the authors also call attention to the different locations, extent, and severity of lesions used in these trials.
As a result of the inconclusive results surrounding the effectiveness of MSC-based therapy for the treatment of stroke in these clinical trials, the authors call for more optimized and well-designed large-sample multicenter studies to evaluate the therapeutic efficacy of MSCs more thoroughly in ischemic stroke.
While the underlying mechanisms of MSC-based therapy for stroke have not been fully explained or understood, a review of several studies has demonstrated that MSCs protect against stroke through multiple mechanisms, including direct differentiation, paracrine effects, and mitochondrial transfer.
Before MSCs can be widely applied in clinical practice, Li et al. highlight several challenges that need to first be considered. These challenges include determining the optimal time for MSC administration during the acute stroke stages, further understanding the best treatment, conditions, and strategies to maximize the regenerative potential of MSCs, identifying the simplest and safest route of MSC delivery, and identifying the best source of MSCs for stroke treatment.
The authors conclude this review by recommending future preclinical and clinical studies that consider the adoption of a well-designed randomized controlled study design and method rigor and intervention measures to determine the effect of MSC therapy in the treatment of stroke.
Even with considering the above recommendations, MSCs continue to demonstrate exciting potential as a means to protect neurons and improve outcomes and overall quality of life for stroke patients.
Ischemic kidney diseases are serious health issues that lead to irreversible loss of kidney function and are commonly associated with high rates of mortality and morbidity. Many of the conditions captured under the term ischemic kidney disease occur as a result of decreased glomerular filtration rate (GFR) caused by vasoconstriction or loss of autoregulation. Ischemic kidney disease, or ischemic renal disease, is a contributing factor anywhere between 6% – 27% of end-stage kidney disease and is most common among patients 50 years old or older.
The progression of these types of kidney diseases is often multifaceted and involves complex hormonal-immunological cellular interactions. Since ischemic kidney disease often involves damage that occurs to many different types of cells, the conditions have often been demonstrated to be resistant to conventional therapy.
Considering mesenchymal stem cells (MSCs) provide renal protection, their anti-inflammatory and immunomodulatory properties are of interest in an effort to better understand how they can be therapeutically used to treat and prevent acute kidney ischemia (AKI).
In this review, Zhu et al. examine recent progress in the use of MSC to prevent kidney diseases, with a specific focus on chronic ischemic kidney disease (CIKD).
When used to treat CIKD, MSCs have been found to achieve renal cellular repair in a number of different ways. Initially, and upon infusion, MSCs home to the injury site and release homing receptors, growth factors, and anti-inflammatory cytokines to the injury site. They also release similar microparticles that promote kidney repair through internalization in other cells, allowing for reduced intrarenal inflammation and the promotion of vascular regeneration.
Examining the results of clinical trials exploring the use of MSC to treat CIKD, and considering patients with diabetes mellitus often develop chronic kidney issues, including diabetic nephropathy (DN), the authors believe the beneficial application of the anti-inflammatory, antioxidant, and immunomodulating features of MSC could help in the treatment of DN.
While Zhu et al. highlights the potential of MSCs in the treatment of CIKD in this review, they also identify potential limitations, including the potential for MSCs to form teratoma or other tumors (to date, no direct evidence of kidney tumor formation has been reported) and exactly how long the effects of MSC on kidney protection will last. As a way to address both potential limitations, the authors recommend longer follow-up times to ensure all potential detrimental effects of MSC use in humans are known and accounted for.
The review concludes that while further studies are needed to discern the chief elements of their actions and to define the optimal type (tissue source, preconditioning), dose, and delivery route, MSCs demonstrate remarkable potential for future treatment of ischemic kidney disease.
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