Figure 3.

Mechanotransduction-based plasticity of engrailed-1 negative fibroblasts (ENFs) at the crossroads between scarring and regeneration. Mechanical tension applied to skin wounds may trigger Yes-associated protein (YAP) mechanotransductive signaling in ENFs and (re)activate Engrailed-1 (En1), thereby giving rise to proscarring En1 positive fibroblasts (EPFs). As a result of this cellular conversion from ENFs to EPFs, skin injuries are sealed with scar matrix following fibrotic wound healing. In contrast, blocking mechanotransduction signaling – with either verteporfin, a YAP inhibitor, or fibroblast-specific transgenic YAP knockout – prevents En1 activation and leads to wound regeneration, with ENFs regrowing skin appendages (such as hair follicles and glands), restoring mechanical strength, and reestablishing healthy basket-weave matrix ultrastructure.