Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

中文翻译：

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晚期伤口巨噬细胞对 Wnt 抑制剂 SFRP4 的吞噬作用驱动慢性 Wnt 活性，促进纤维化皮肤愈合。


人类和小鼠皮肤受伤通常会导致纤维化疤痕，但小鼠受伤模型伤口诱导的毛发新生（WIHN）经常会导致再生修复反应。在这里，我们在半再生和纤维化 WIHN 伤口的单细胞 RNA 测序比较中显示，巨噬细胞中吞噬/溶酶体基因的表达增加与纤维化伤口中纤维化肌成纤维细胞的优势相关。研究表明，伤口后期的巨噬细胞通过吞噬真皮 Wnt 抑制剂 SFRP4 来驱动纤维化，从而建立持久的 Wnt 活性。相应地，吞噬作用的废除导致短暂的 Wnt 活性和更具再生性的愈合。 SFRP4 的吞噬作用是整合素介导的，并且依赖于 SFRP4 与纤连蛋白 EDA 剪接变体的相互作用。在人类皮肤病化脓性汗腺炎中，巨噬细胞对 SFRP4 的吞噬作用与纤维化伤口修复相关。这些结果表明，巨噬细胞可以通过吞噬作用调节关键信号通路，从而改变皮肤伤口愈合的命运。