Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs)

• ? Paradigm I: the haematopoietic niche
• ? Paradigm II: engraftment/differentiation
  • ‐ Early observations on engraftment and differentiation
  • ‐ Technical challenges in testing paradigm II
  • ‐ The impetus to test the paradigm II in clinical trials
  • ‐ Tests of the paradigm II with local administrations
  • ‐ Tests of paradigm II with systemic infusion
• ? Paradigm III: transient ‘quasi‐niches’
  • ‐ Unusual features of MSCs in culture
  • ‐ Cross‐talk with injured tissues
  • ‐ Modulation of inflammation in paradigm III
  • ‐ Modulation of apoptosis in paradigm III
  • ‐ Modulation of immune reactions
  • ‐ Paradigm III and the similarities to paradigm I
• ? Conclusions/perspectives
  • ‐ Why is administration of MSCs beneficial?
  • ‐ Better assays for the potency of MSCs?
  • ‐ Are MSCs pericytes?
  • ‐ Therapies with recombinant proteins?
  • ‐ Additional questions in developing therapies with MSCs

In this review, we focus on the adult stem/progenitor cells that were initially isolated from bone marrow and first referred to as colony forming units‐fibroblastic, then as marrow stromal cells and subsequently as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). The current interest in MSCs and similar cells from other tissues is reflected in over 10,000 citations in PubMed at the time of this writing with 5 to 10 new publications per day. It is also reflected in over 100 registered clinical trials with MSCs or related cells ( http//www.clinicaltrials.gov ). As a guide to the vast literature, this review will attempt to summarize many of the publications in terms of three paradigms that have directed much of the work: an initial paradigm that the primary role of the cells was to form niches for haematopoietic stem cells (paradigm I); a second paradigm that the cells repaired tissues by engraftment and differentiation to replace injured cells (paradigm II); and the more recent paradigm that MSCs engage in cross‐talk with injured tissues and thereby generate microenvironments or ‘quasi‐niches’ that enhance the repair tissues (paradigm III).