Mechanisms of mesenchymal stem/stromal cell function

Abstract

The past decade has seen an explosion of research directed toward better understanding of the mechanisms of mesenchymal stem/stromal cell (MSC) function during rescue and repair of injured organs and tissues. In addition to delineating cell-cell signaling and molecular controls for MSC differentiation, the field has made particular progress in defining several other mechanisms through which administered MSCs can promote tissue rescue/repair. These include: 1) paracrine activity that involves secretion of proteins/peptides and hormones; 2) transfer of mitochondria by way of tunneling nanotubes or microvesicles; and 3) transfer of exosomes or microvesicles containing RNA and other molecules. Improved understanding of MSC function holds great promise for the application of cell therapy and also for the development of powerful cell-derived therapeutics for regenerative medicine. Focusing on these three mechanisms, we discuss MSC-mediated effects on immune cell responses, cell survival, and fibrosis and review recent progress with MSC-based or MSC-derived therapeutics.

Keywords: Exosome; Mesenchymal stem cell; Microvesicle; Mitochondria transfer; Multipotent stromal cell; Paracrine; Tunneling nanotube.

Fig. 1

MSCs rescue and/or repair injured cells and tissues by diverse mechanisms. a Differentiation into replacement cell types. b Rescue of damaged or dying cells through cell fusion. c Secretion of paracrine factors such as growth factors, cytokines, and hormones. VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor, ANG1 angiopoietin-1, IL-11 interleukin-11, PGE2 prostaglandin E2, TSG-6 TNF-stimulated gene-6, SDF-1 stromal-derived factor-1, HGF hepatocyte growth factor, IGF-1 insulin-like growth factor-1. d Transfer of organelles (e.g., mitochondria) and/or molecules through tunneling nanotubes (TNTs). Ca ²⁺ calcium, Mg ²⁺ magnesium. e MSC-mediated transfer of proteins/peptides, RNA, hormones, and/or chemicals by extracellular vesicles such as exosomes or microvesicles. Exosomes are generated through the endocytic pathway and released through exocytosis. By contrast, microvesicles are produced by cell surface budding and released directly from the plasma membrane. Note that the figure is not drawn to scale. Also, use of mechanisms a–e is not equivalent. For example, for MSCs administered intravenously, use of mechanism c is likely more relevant than are mechanisms (a) or (b)