Preventing <i>Engrailed-1</i> activation in fibroblasts yields wound regeneration without scarring

Abstract

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. <i>Engrailed-1</i> lineage-positive fibroblasts (EPFs) are known to function in scarring, but <i>Engrailed-1</i> lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating <i>Engrailed-1</i> expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives <i>Engrailed-1</i> activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents <i>Engrailed-1</i> activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).