Challenges and Controversies in Human Mesenchymal Stem Cell Therapy

Challenges and Controversies in Human Mesenchymal Stem Cell Therapy

Mesenchymal stem cells have become popular in terms of clinical interest because of their potential in stem cell transplantation. A lot of clinical trials using mesenchymal stem cells have been achieved but many are still in the pipeline under scrutiny. Mesenchymal stem cell therapy risk should be considered in terms of long-lasting observations instead of fast results. Growing evidence from recent studies strongly suggests that the release of extracellular vesicles with mRNAs, regulatory miRNAs, multiple bioactive proteins and compounds, and the production and secretion of a large number of regulatory substances promote mesenchymal stem cell differentiation and cell replacement. The main therapeutic effects of mesenchymal stem cells are now attributed to stimulation of endogenous repair processes in the injured tissues by secreted factors as well as immunomodulatory response.

MSCs secretome

The cellular heterogeneity of mesenchymal stem cells makes consistent conclusions on therapeutic potential seem difficult as results will depend on the different tissue origins as well as harvesting/ culture procedures. This complex nature also makes mesenchymal stem cells an interesting candidate for research. A major issue regarding mesenchymal stem cell therapy research is mostly inadequate culture protocols and validation of optimal isolation and culture protocols is still needed. Aside from that, this article mainly discusses the potential challenges of mesenchymal stem cell administration in vivo. In particular, we focus on graft vs host disease, cardiologic, neural, and orthopedic issues.

Mesenchymal stem cells in Graft-versus-Host Disease

Graft-versus-host disease generally accompanies allogeneic stem cell transplantation in many patients. In GvHD treatment cases, corticosteroids are used, but not effectively. Immunomodulatory properties of mesenchymal stem cells have suggested their role in GvHD treatment for patients who are unresponsive to steroids. Although the inflammatory response reduction is noticed after mesenchymal stem cell transplantation, the downregulation of immune response could augment infection chances, especially in patients receiving immunosuppressive therapy after allogeneic stem cell transplantation. It was reported that the mesenchymal stem cell infusion might also constrain antimicrobial immune response. These studies highlight that mesenchymal stem cell transplantation for GvHD prevention is relatively safe and efficient in steroid-unresponsive GvHD, but infections remain a major patient risk.

Mesenchymal stem cells in Cardiology

Since heart tissue exhibits limited endogenous potential for cell proliferation and repair, multiple stem cell-based approaches have already been in several preclinical pipelines on animal and human models for cardiovascular diseases. Adult stem cells like mesenchymal stem cells have been indicated as one of the most promising candidates for myocardial repair and regeneration. Although mesenchymal stem cells exhibit pro-chondrogenic and osteogenic differentiation potential, several studies have provided evidence that in optimal culture conditions, mesenchymal stem cells also give rise to other specialized cell types including cardiomyocytes and endothelial cells. As for the limitations and concerns, the differentiating capacity of mesenchymal stem cells into endothelial and cardiac cells in vivo has not been fully confirmed and moreover, it is hard to confirm the presence of implanted, integrated cells in vivo, due to the lack of specific mesenchymal stem cell markers. However, recent evidence strongly indicates the predominant paracrine activity of mesenchymal stem cells after transplantation, to promote cardiac cell survival, proliferation, and differentiation. These functions are promoted by mesenchymal stem cell-derived secretome and extracellular vesicles. Although mesenchymal stem cells represent a safe population of stem cells with nearly no endogenous teratogenic risks, they may potentially lead to some adverse effects. The few reported concerns are generally related to possible proarrhythmic capacity in heart tissues.

Mesenchymal stem cells in Neurology

Multiples studies are being undertaken for mesenchymal stem cell transplantation in various neurological diseases like autism, stroke, cerebral palsy, etc. However, several data show that mesenchymal stem cells are ineffective in the case of the same. In the case of amyotrophic lateral sclerosis phase I study, the results did not show significant positive outcomes by using exogenous mesenchymal stem cells implanted in the spinal cord. The main conclusion in most of the clinical trials for ALS came out as a safety assurance in terms of mesenchymal stem cell applications. In one study, where bone-marrow-derived mesenchymal stem cells were used intrathecally, beneficial outcome was visible only in few patients. In another report, intramuscularly and intrathecally transplanted mesenchymal stem cells from the bone marrow were reported safe and aided in the stimulation of autologous neurotrophic factors release. In case of stroke, the delivery route of mesenchymal stem cell infusion is crucial and one should be aware of the process to assure the safety of the patient. Some studies report that cell clump formation before injection increases with the increasing cell storage time in suspension. In addition, mesenchymal stem cells might elicit vascular obstructions after intravascular delivery if they are cultured in monolayer culture in vitro as their size increases along with the passage number. A better solution is the 3D spheroid culture in vitro which makes mesenchymal stem cells smaller again. Further research is also required to help mesenchymal stem cells cross the blood-brain barrier as this limitation makes the engrafted numbers too less as compared to the infused numbers.

Mesenchymal stem cells in Orthopedics

Numerous studies of orthopedic diseases have reported the multipotency of mesenchymal stem cells to differentiate into a variety of lineages like muscle, bone, cartilage, and tendon. Although initial assumptions were that mesenchymal stem cells exert therapeutic effects by cell replacement, recent discoveries suggest the role of paracrine functions for tissue repair and immunomodulatory properties. While many studies have been done regarding the role of mesenchymal stem cells in osteoarthritis, the results have been inconsistent and the optimal dose/ route of cell administration is still awaiting establishment. Despite studies in the field of bone and cartilage regeneration, enough randomized controlled trials are quite lacking when it comes to understanding the role of mesenchymal stem cells. Besides that, there is also a dire need for optimizing the therapeutic dose of cells, co-adjuvants, and source of harvesting.
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