Human Mesenchymal Stem Cells Self-Renew and Differentiate According to a Deterministic Hierarchy

Abstract

BackgroundMesenchymal progenitor cells (MPCs) have been isolated from a variety of connective tissues, and are commonly called “mesenchymal stem cells” (MSCs). A stem cell is defined as having robust clonal self-renewal and multilineage differentiation potential. Accordingly, the term “MSC” has been criticised, as there is little data demonstrating self-renewal of definitive single-cell-derived (SCD) clonal populations from a mesenchymal cell source.Methodology/Principal FindingsHere we show that a tractable MPC population, human umbilical cord perivascular cells (HUCPVCs), was capable of multilineage differentiation in vitro and, more importantly, contributed to rapid connective tissue healing in vivo by producing bone, cartilage and fibrous stroma. Furthermore, HUCPVCs exhibit a high clonogenic frequency, allowing us to isolate definitive SCD parent and daughter clones from mixed gender suspensions as determined by Y-chromosome fluorescent in situ hybridization.Conclusions/SignificanceAnalysis of the multilineage differentiation capacity of SCD parent clones and daughter clones enabled us to formulate a new hierarchical schema for MSC self-renewal and differentiation in which a self-renewing multipotent MSC gives rise to more restricted self-renewing progenitors that gradually lose differentiation potential until a state of complete restriction to the fibroblast is reached.

Reconstruction of human elastic cartilage by a CD44 + CD90 + stem cell in the ear perichondrium

“…This is attributable to the low frequencies of highly clonogenic stem cells, a common challenge in the field of mesenchymal stem cell-related research (31,32). Here, we have successfully identified and isolated a human stem/progenitor cell population (CSPCs) existing in the auricular perichondrium by combinations of CD44 and CD90 markers.…”

Concise Review: Wharton's Jelly: The Rich, but Enigmatic, Source of Mesenchymal Stromal Cells

“…One exception to this was the work reported by Sarugaser et al 38 that did show, at the single cell clonal level, that true self‐renewing cells existed in the perivascular tissue of the cord that gave rise to multilineage offspring—work that was only possible due to the high CFU‐F frequency in the cell populations extracted from the perivascular tissue (see Fig. 5 and “Cell Phenotype” above right).…”

Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

“…Human BM MSC are a heterogeneous population of progenitors at different stages of commitment and with different expansion potential [1], as shown in clonal experiments [2]. Although this heterogeneity was already described by Friedenstein in the 1980s [3] and despite recent interest on the hierarchical relationship among different MSC populations [4,5], the mechanisms regulating MSC self-renewal are still largely unknown.…”