MSCs: Changing hypotheses, paradigms, and controversies on mechanisms of action in repairing tissues

Abstract

Research on mesenchymal stromal cells (MSCs) has moved at a rapid pace that has been driven by unexpected discoveries about the biology of the cells and their beneficial effects in multiple models for human diseases. There are currently at least three paradigms as to how the MSCs can repair tissues: (I) by engrafting and serving as a niche for stem/progenitor cells; (II) by engrafting and differentiating to repair damaged tissues; and (III) by temporarily engrafting in injured tissues, engaging in extensive "cross-talk" triggered by signals from the injured tissues, and producing factors that both limit injury to the tissues by multiple effects such as modulating excessive inflammatory and immune responses and enhance repair by providing a niche that stimulates the propagation and differentiation of tissue-endogenous stem/progenitor cells. In the background of research to support each of the paradigms is a series of controversies that have not been resolved in spite of the efforts of the thousands of dedicated scientists who have made major contributions to the field. We will review here just a few of these controversies with conclusions that reflect some of our own biases.