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

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 a (PDGFRa) gene mutations, we examine cell fates during skin wound heal-ing. Elevated PDGFRa signaling increases proliferation but unexpectedly delays the fibroblast-to-myofibro-blast transition, suggesting that PDGFRa must be downregulated for myofibroblast differentiation. In contrast, deletion of PDGFRa decreases proliferation and myofibroblast differentiation by reducing serum response factor (SRF) nuclear localization. Consequences of SRF deletion resemble PDGFRa deletion, but deletion of two SRF coactivators, MRTFA and MRTFB, specifically eliminates myofibroblasts. Our findings suggest a scenario where PDGFRa signaling initially supports proliferation of fibroblast progenitors to expand their number during early wound healing but, later, PDGFRa downregulation facilitates fibroblast dif-ferentiation into myofibroblasts.

Automated summary

This study investigates the role of PDGF receptor a (PDGFRa) signaling in the differentiation of fibroblasts into myofibroblasts during skin wound healing. The results show that elevated PDGFRa signaling increases fibroblast proliferation but delays the fibroblast-to-myofibroblast transition. On the other hand, deletion of PDGFRa decreases cell proliferation and myofibroblast differentiation. Additionally, the coactivators MRTFA and MRTFB are found to be crucial for myofibroblast formation.