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

Science (New York, N.Y.) 2021 Apr 23

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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). Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Shamik Mascharak, Heather E desJardins-Park, Michael F Davitt, Michelle Griffin, Mimi R Borrelli, Alessandra L Moore, Kellen Chen, Bryan Duoto, Malini Chinta, Deshka S Foster, Abra H Shen, Michael Januszyk, Sun Hyung Kwon, Gerlinde Wernig, Derrick C Wan, H Peter Lorenz, Geoffrey C Gurtner, Michael T Longaker. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science (New York, N.Y.). 2021 Apr 23;372(6540)