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

Science. 2021 Apr 23;372(6540):eaba2374. doi: 10.1126/science.aba2374.


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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cicatrix / pathology*
  • Cicatrix / prevention & control
  • Fibroblasts / physiology*
  • Fibroblasts / transplantation
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-yes / antagonists & inhibitors
  • Proto-Oncogene Proteins c-yes / genetics
  • Proto-Oncogene Proteins c-yes / metabolism
  • Regeneration*
  • Signal Transduction
  • Skin / injuries*
  • Stress, Mechanical
  • Transcriptional Activation
  • Transcriptome
  • Verteporfin / pharmacology
  • Wound Healing*


  • En1 protein, mouse
  • Homeodomain Proteins
  • Verteporfin
  • Proto-Oncogene Proteins c-yes
  • Yes1 protein, mouse