The Use of MSCs, iPSCs, and EVs in the Repair of Human MSK Tissues: Is Ultimate Success Dependent on Developing Excellent Implant Materials as Well as Creating an Optimal Environment for Implantation? What Is the Rationale for These Choices?

It has been >35 years since the cells described as mesenchymal stem cells (MSCs) were reported to have multi-lineage potential, which opened the possibility that they could be used to repair injured or diseased musculoskeletal tissues. Since that time, similar cells have been isolated from many tissues, again raising expectations that they could be used to repair or regenerate many types of tissues. While some progress in using these cells, as well as induced pluripotent stem cells (iPSCs), to facilitate the repair of tissues has been achieved, an emerging body of literature would suggest that the cells in question facilitate repair via released extracellular vesicles (EVs) that contain a cargo of molecules which induce endogenous cells to do the actual repair. How the "stemness" of the cells is involved in such processes remains to be elucidated. While progress in the repair of compromised tissues has been obtained, from some perspectives, the progress has been challenging and successful translation to patients has been slow. In part, this has been due to considerable emphasis being placed on the cells or EVs, and not as much on the environments in which they are implanted. However, successful outcomes likely depend on both the development of optimized materials to be implanted and an environment that is conducive to success after implantation. This perspective article reviews some of the options regarding the implantable materials and the variables or factors that could impact the local environment's suitability for success following implantation. In addition, attempts are made to reconcile the designation of endogenous cells labeled MSCs and their potential roles as regulators of tissue integrity in vivo.