巨噬细胞通过 TNF 诱导 AKT/β-连环蛋白依赖性 Lgr5 干细胞激活和毛囊再生。
Macrophages induce AKT/β-catenin-dependent Lgr5 stem cell activation and hair follicle regeneration through TNF.
机构信息
School of Life Sciences, Tsinghua University, Beijing 100084, China.
The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
出版信息
Nat Commun. 2017 Mar 27;8:14091. doi: 10.1038/ncomms14091.
Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen-anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5 HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5 HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.
皮肤干细胞可以再生表皮附属物；然而，由于损伤而丢失的毛囊（HF）几乎无法再生。在这里，我们表明伤口中的巨噬细胞激活 HF 干细胞，导致伤口周围的休止期-生长期过渡（TAT）和新的 HF 再生，主要通过 TNF 信号通路。TNF 敲除和过表达都减弱了伤口中的 HF 新生，这表明 TNF 以剂量依赖的方式诱导 HF 新生，这与 TNF 在体外诱导表皮干细胞中 AKT 信号通路一致。TNF 诱导的 β-catenin 积累依赖于 AKT 而不是 Wnt 信号通路。PI3K/AKT 的抑制阻止了脱毛诱导的 HF TAT。值得注意的是，Lgr5 HF 干细胞中的 Pten 缺失导致 HF TAT 不依赖于损伤，并在受伤后促进 HF 新生。因此，我们的结果表明，巨噬细胞-TNF 诱导的 Lgr5 HF 干细胞中的 AKT/β-catenin 信号通路在促进受伤后 HF 循环和新生中起着关键作用。
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