Dermal αSMA + myofibroblasts orchestrate skin wound repair via β1 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. αSMA 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 αSMA 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 αSMA myofibroblasts is surprisingly dispensable for wound repair. In contrast, we show that β1 integrin from αSMA myofibroblasts, but not TGFβRII, is essential for wound healing, facilitating contractility, reepithelization, and vascularization. Collectively, our study provides evidence for the functions of myofibroblasts in β1 integrin-mediated wound repair with potential implications for treating chronic non-healing wounds.