Cell-based therapies have the potential to revolutionize current treatments for diseases with high prevalence and related economic and social burden. 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. strong class=”kwd-title” Keywords: anoikis, cell survival, cell therapy, cell transplantation, extracellular vesicles, hypoxia, mesenchymal stromal cells, regenerative medicine 1. Introduction Preclinical investigations have encouraged the development of novel cell therapy dBET57 approaches to promote tissue Rabbit Polyclonal to ASC regeneration . However, translational studies have demonstrated mixed results . The moderate advantage seen in medical trials is, a minimum of in part, because of the limited viability from the transplanted cells, whatever the origin from the donor cells as well as the degenerative disease under analysis. In fact, as much as 99% of grafted cells may perish 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. Here 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. Moreover, we discuss the multiple strategies that have been used to attempt to enhance cell therapys beneficial effects in regenerative medicine, with particular emphasis on mesenchymal stromal cell therapy. 2. Challenges to Successful Mesenchymal Stromal Cell Transplantation Nearly 600 cell therapy clinical studies dBET57 involving mesenchymal stromal cells (MSCs) are recorded in the National dBET57 Institutes of Health (NIH) clinical trial registry (Available online: www.clinicaltrials.gov). MSCs have been used for their ability to promote tissue repair and wound healing , for immunomodulation , and as a vehicle for targeted cancer therapies for their tumor homing properties [7,8,9]. Age and pathological conditions are among the factors affecting the therapeutic potential of cell therapy . In fact, aging and disease are linked to perturbations at the genomic, epigenomic, and proteomic levels , which negatively influence MSCs functional activities . Cell proliferation and differentiation, paracrine signaling, and the ability to promote injury repair can be deteriorated in MSCs isolated from older subjects, in patients affected by diabetes, obesity, and cardiovascular disorders [10,13,14,15]. Equally, age and disease cause changes in the recipient site in which the cells are administered, possibly attenuating the efficacy of both autologous and allogeneic cell based therapies . The limited success of the majority of the completed protocols underscores the need to minimize massive MSC death after transplant for improving the efficacy of cell transplantation procedures. During the dBET57 transplantation procedure, MSCs undergo different processes that can potentially affect their performance and be responsible for the high attrition of donor cells upon transplant. In particular, transplanted cell survival may be affected by: (1) anoikis, due to the need to detach anchorage-dependent cells from their substrate for injection and to cellular tensegrity loss after implantation; (2) mechanical stress during the implantation procedure; (3) oxygen and nutrient deprivation, because of low diffusion into vascularized conditions; and (4) inflammation-related elements, from the feasible activation from the sponsor immune system response. 2.1. CellCExtracellular Matrix Relationships Clinical applications of MSCs derive from single cell suspension system, in which relationships between cells as well as the extracellular matrix (ECM) are dropped and adhesion indicators are downregulated with consequent apoptosis, better thought as anoikis. Such cell loss of life could.