Gene

Mechanotransduction

Cell biology

Biology

Transgene

Homeobox

Receptor

Genetically modified mouse

Regeneration (biology)

Knockout mouse

Immunology

Genetics

Anatomy

In vitro

engrailed

Medicine

Fibroblast

Gene expression

Wound healing

Pathology

Science

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage-positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 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 Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 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 Engrailed-1 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).

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

Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring