Dermal alpha SMA(+) myofibroblasts orchestrate skin wound repair via beta 1 integrin and independent of type I collagen production

Skin wound repair is essential for organismal survival and failure of which leads to non-healing wounds, a leading health issue worldwide. However, mechanistic understanding of chronic wounds remains a major challenge due to lack of appropriate genetic mouse models. alpha SMA(+) myofibroblasts, a unique class of dermal fibroblasts, are associated with cutaneous wound healing but their precise function remains unknown. We demonstrate that genetic depletion of alpha SMA(+) myofibroblasts leads to pleiotropic wound healing defects, including lack of reepithelialization and granulation, dampened angiogenesis, and heightened hypoxia, hallmarks of chronic non-healing wounds. Other wound-associated FAP(+) and FSP1(+) fibroblasts do not exhibit such dominant functions. While type I collagen (COL1) expressing cells play a role in the repair process, COL1 produced by alpha SMA(+) myofibroblasts is surprisingly dispensable for wound repair. In contrast, we show that beta 1 integrin from alpha SMA(+) myofibroblasts, but not TGF beta RII, is essential for wound healing, facilitating contractility, reepithelization, and vascularization. Collectively, our study provides evidence for the functions of myofibroblasts in beta 1 integrin-mediated wound repair with potential implications for treating chronic non-healing wounds.