Abstract
Cell-based therapies have the potential to revolutionize current treatments for diseases with high prevalence and related economic and social burden. Unfortunately, clinical trials have made only modest improvements in restoring normal function to degenerating tissues. This limitation is due, at least in part, to the death of transplanted cells within a few hours after transplant due to a combination of mechanical, cellular, and host factors. In particular, mechanical stress during implantation, extracellular matrix loss upon delivery, nutrient and oxygen deprivation at the recipient site, and host inflammatory response are detrimental factors limiting long-term transplanted cell survival. The beneficial effect of cell therapy for regenerative medicine ultimately depends on the number of administered cells reaching the target tissue, their viability, and their promotion of tissue regeneration. Therefore, strategies aiming at improving viable cell engraftment are crucial for regenerative medicine. Here we review the major factors that hamper successful cell engraftment and the strategies that have been studied to enhance the beneficial effects of cell therapy. Moreover, we provide a perspective on whether mesenchymal stromal cell-derived extracellular vesicle delivery, as a cell-free regenerative approach, may circumvent current cell therapy limitations.
Highlights
Preclinical investigations have encouraged the development of novel cell therapy approaches to promote tissue regeneration [1]
Clinical applications of mesenchymal stromal cells (MSCs) are based on single cell suspension, in which interactions between cells and the extracellular matrix (ECM) are lost and adhesion signals are downregulated with consequent apoptosis, better defined as anoikis
Poor cell survival after transplantation, which is due to a combination of mechanical, cellular, and host factors, limits cell therapy efficacy
Summary
Preclinical investigations have encouraged the development of novel cell therapy approaches to promote tissue regeneration [1]. The moderate benefit seen in clinical trials is, at least in part, due to the limited viability of the transplanted cells, regardless of the origin of the donor cells and the degenerative disease under investigation. Up to 99% of grafted cells may die within the first few hours after transplantation, due to the rigors of the microenvironment they encounter upon transplant [3,4]. The cause of rapid death of the transplanted cells is likely to be a combination of different environmental stresses cells face both before and after transplantation and implantation. We review the major obstacles to long-term cell survival at the implantation site that are slowing progress and translational clinical research in the cell therapy field. We discuss the multiple strategies that have been used to attempt to enhance cell therapy’s beneficial effects in regenerative medicine, with particular emphasis on mesenchymal stromal cell therapy
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