Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing

SUMMARY

Fibroblasts differentiate into myofibroblasts by acquiring new contractile function. This is important for tissue repair, but it also contributes to organ fibrosis. Platelet-derived growth factor (PDGF) promotes tissue repair and fibrosis, but the relationship between PDGF and myofibroblasts is unclear. Using mice with lineage tracing linked to PDGF receptor α (PDGFRα) gene mutations, we examine cell fates during skin wound healing. Elevated PDGFRα signaling increases proliferation but unexpectedly delays the fibroblast-to-myofibroblast transition, suggesting that PDGFRα must be downregulated for myofibroblast differentiation. In contrast, deletion of PDGFRα decreases proliferation and myofibroblast differentiation by reducing serum response factor (SRF) nuclear localization. Consequences of SRF deletion resemble PDGFRα deletion, but deletion of two SRF coactivators, MRTFA and MRTFB, specifically eliminates myofibroblasts. Our findings suggest a scenario where PDGFRα signaling initially supports proliferation of fibroblast progenitors to expand their number during early wound healing but, later, PDGFRα downregulation facilitates fibroblast differentiation into myofibroblasts.

In brief

Yao et al. use lineage-tracing and wound-healing experiments in mice to investigate functions of the PDGFRα signaling pathway in the fibroblast-to-myofibroblast transition. Their analysis indicates an early role for PDGFRα-SRF signaling to support fibroblast proliferation, followed by PDGFRα downregulation and a transition to MRTF-SRF control over myofibroblast differentiation.

Graphical Abstract