Investigating the Fibroblastic Origin of Skin-Derived Precursors and the Role Of CCN2 as a Mediator of Myofibroblastic Differentiation

Skin-derived precursors (SKPs) are defined as multipotent spheroid-forming cells cultured from the dermis that express markers of neural crest origin. Recent evidence suggests that tissue fibrosis can occur through the differentiation of progenitor cells into smooth muscle-like myofibroblasts. CCN2, a marker and mediator of fibrosis, is highly expressed during myofibroblast differentiation and is required for skin fibrogenesis. Here, I clarify the cellular origin of SKPs, and the molecular contribution of CCN2 in the myofibroblastic differentiation of SKPs. Using lineage tracing, I show that SKPs originate primarily from Col1a2-expressing dermal fibroblasts. Furthermore, I show that differentiation of SKPs into myofibroblasts requires the FAK and SRF-mediated induction of CCN2: Col1a2-specific deletion of CCN2 impairs the ability of SKPs to differentiate into α-SMA-expressing myofibroblasts. Taken together, these results suggest that collagen-producing fibroblasts possess inherent plasticity, and that CCN2 is a downstream mediator of the ability of SKPs to differentiate into myofibroblasts.