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

Abstract

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).

Fig 1

Schematic summarizing three evolving paradigms for the repair of tissues by MSCs. The morphology of a small number of adherent cells from bone marrow suggested the paradigm that the cells served as a niche for haematopoietic cells (paradigm I). The ready differentiation of the cells in culture suggested that the cells could repair tissues by engrafting and differentiating (paradigm II). Clinical trials using the cells to improve bone marrow transplants unexpectedly demonstrated that they improved graft-versus-host diseases in a few patients and thereby drew attention to their immune modulatory properties. Functional improvement without significant engraftment in animal models and a few patients suggested that MSCs enhanced repair by forming microenvironments or ‘quasi-niches’ (paradigm III).

Fig 2

Effects of human MSCs and recombinant TSG-6 in mice (NOD/scid) with myocardial infarcts (MI). (A) Schematic illustrating the progressive damage to the myocardium following myocardial infarction. The ischemia triggers invasion by inflammatory cells. The inflammatory cells and the matrix metalloproteinases they release accentuate damage to the myocardium. TSG-6 synthesized by MSCs or recombinant TSG-6 limits the injury and thereby enhances repair. Reproduced with permission and modified from [100]. (B) Protective/reparative properties of MSCs and TSG-6 in MI. Three weeks after permanent ligation of the anterior descending coro nary artery in mice to produce MI, each heart was cut from the apex through base into over 400 sequential 5 μm sections and stained with Masson Trichrome. Every 20th section is shown. Symbols: Normal, naïve mice; –, MI only; hMSCs, 2 × 10⁶ hMSCs infused intravenously (i.v.) 1 hr after MI; scr siRNA, 2 × 10⁶ hMSCs transduced with scrambled siRNA infused i.v. 1 hr after MI; TSG-6 siRNA, 2 × 10⁶ hMSCs transduced with TSG-6 siRNA infused i.v. 1 hr after MI; rhTSG-6, 30 μg recombinant TSG-6 protein infused i.v. 1 hr and again 24 hrs after MI. Reproduced with permission from [62].

Fig 3

Schematic for MSCs providing a niche for haematopoietic stem cells as in paradigm I and modulating excessive inflammatory and immune responses as in paradigm III. One effect of administered MSCs is to introduce a negative feedback into the excessive responses of tissues to sterile injury. They may also enhance repair by increasing propagation and differentiation of tissue endogenous stem/progenitor cells (not shown). Some of the therapeutic effects of MSCs may require direct cell-to-cell contact and transfer of components such as mitochondria.