No Identical “Mesenchymal Stem Cells” at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels

Abstract

Summary: A widely shared view reads that mesenchymal stem/stromal cells (“MSCs”) are ubiquitous in human connective tissues, can be defined by a common in vitro phenotype, share a skeletogenic potential as assessed by in vitro differentiation assays, and coincide with ubiquitous pericytes. Using stringent in vivo differentiation assays and transcriptome analysis, we show that human cell populations from different anatomical sources, regarded as “MSCs” based on these criteria and assumptions, actually differ widely in their transcriptomic signature and in vivo differentiation potential. In contrast, they share the capacity to guide the assembly of functional microvessels in vivo, regardless of their anatomical source, or in situ identity as perivascular or circulating cells. This analysis reveals that muscle pericytes, which are not spontaneously osteochondrogenic as previously claimed, may indeed coincide with an ectopic perivascular subset of committed myogenic cells similar to satellite cells. Cord blood-derived stromal cells, on the other hand, display the unique capacity to form cartilage in vivo spontaneously, in addition to an assayable osteogenic capacity. These data suggest the need to revise current misconceptions on the origin and function of so-called “MSCs,” with important applicative implications. The data also support the view that rather than a uniform class of “MSCs,” different mesoderm derivatives include distinct classes of tissue-specific committed progenitors, possibly of different developmental origin. : Bianco, Riminucci, Robey, and colleagues have provided evidence that “mesenchymal stem/stromal cells” (according to current “jargon”), derived from different sources (bone marrow, muscle, cord blood) vary widely in their transcriptional profile, and their differentiation capacity as assessed by in vitro assays and in vivo transplantation assays. Bone marrow “MSCs” form bone and support hematopoiesis, but are not myogenic; muscle “MSCs” are spontaneously myogenic, but do not form bone; cord blood “MSCs” are inherently chondrogenic, and do form bone, but do not support hematopoiesis. However, despite their significant differences, “MSCs” from different sources are capable of forming pericytes when co-transplanted with endothelial cells in vivo, resulting in the development of functional blood vessels. These findings are important not only in understanding the biology of specific tissues, but also from an applicative clinical angle. Key words: bone marrow stromal cell, mesenchymal stem cell, skeletal progenitors, myogenic progenitors, transplantation, differentiation, in vivo assays, hematopoietic microenvironment