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).

皮肤疤痕是成人伤口愈合的最终结果，对组织形态和功能有害。已知Engrailed-1谱系阳性成纤维细胞 (EPF) 在瘢痕形成中起作用，但Engrailed-1谱系阴性成纤维细胞 (ENF) 的特征仍然很差。使用细胞移植和转基因小鼠模型，我们确定了一个真皮 ENF 亚群，该亚群通过在成人伤口愈合过程中激活Engrailed-1表达来产生出生后衍生的 EPF。通过研究 ENF 对基材力学的反应，我们发现机械张力驱动Engrailed-1通过典型的机械转导信号激活。最后，我们发现，用 Yes 相关蛋白 (YAP) 抑制剂 Verteporfin 或成纤维细胞特异性转基因 YAP 敲除阻断机械转导信号可防止Engrailed-1激活并通过 ENF 促进伤口再生，同时恢复皮肤附件、超微结构、和机械强度。这一发现表明产后伤口愈合有两种可能的结果：纤维化反应（EPF 介导）和再生反应（ENF 介导）。