Spiny mice (Acomys cahirinus) are terrestrial mammals that evolved unique scar-free regenerative wound-healing properties. Myofibroblasts (MFs) are the major scar-forming cell type in skin. We found that following traumatic injury to ear pinnae, MFs appeared rapidly in both Acomys and mouse yet persisted only in mouse. The timing of MF loss in Acomys correlated with wound closure, blastema differentiation, and nuclear localization of the Hippo pathway target protein Yap. Experiments in vitro revealed an accelerated PP2A-dependent dephosphorylation activity that maintained nuclear Yap in Acomys dermal fibroblasts (DFs) and was not detected in mouse or human DFs. Treatment of Acomys in vivo with the nuclear Yap-TEAD inhibitor verteporfin prolonged MF persistence and converted tissue regeneration to fibrosis. Forced Yap activity prevented and rescued TGF-β1-induced human MF formation in vitro. These results suggest that Acomys evolved modifications of Yap activity and MF fate important for scar-free regenerative wound healing in vivo.

多刺小鼠 ( Acomys cahirinus ) 是陆生哺乳动物，进化出独特的无疤痕再生伤口愈合特性。肌成纤维细胞 (MF) 是皮肤中主要的疤痕形成细胞类型。我们发现耳廓外伤后，MFs 在Acomys和小鼠中迅速出现，但仅在小鼠中持续存在。Acomys中 MF 丧失的时间与 Hippo 通路靶蛋白 Yap 的伤口闭合、胚芽分化和核定位相关。体外实验显示加速的 PP2A 依赖性去磷酸化活性维持Acomys真皮成纤维细胞 (DF) 中的核 Yap，而在小鼠或人类 DF 中未检测到。体内 Acomys 的治疗使用核 Yap-TEAD 抑制剂 Verteporfin 可延长 MF 持续时间并将组织再生转化为纤维化。强制 Yap 活性在体外预防和挽救了 TGF-β1 诱导的人 MF 形成。这些结果表明，Acomys进化出对 Yap 活性和 MF 命运的修饰，这对于体内无疤痕再生伤口愈合很重要。