Abstract
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.
Highlights
Skin stem cells can regenerate epidermal appendages; hair follicles (HF) lost as a result of injury are barely regenerated
Osaka et al observed the crucial role of macrophages in Wound-induced hair anagen re-entry/growth (WIH-A), Ralf Paus did pioneering work to investigate hair cycling and its related immune fluctuations[2,12,13,39,40,41,42,43,44,45,46], and Cotsarelis and colleagues contributed landmark WIH follicle neogenesis (WIHN) studies describing the important role of Wnt in WIHN
Perez-Moreno and colleagues found that skin-resident macrophages function as important mesenchymal regulators of HF stem cells function under physiological conditions, which identifies a novel link between macrophages and HF cycling[12]
Summary
Ly6C þ macrophages are required for WIH-A and WIHN. We investigated the mechanism underlying WIH-A, in which. TNF is a crucial mediator of macrophage-induced HF TAT. To identify mediators of macrophage-induced HF TAT, we performed a microarray analysis of Ly6C þ inflammatory macrophages (Ly6C þ /F4/80 þ ), CX3CR1 þ (CX3CR1 þ /F4/80 þ ) resident a e
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