Macrophages induce AKT/β-catenin-dependent Lgr5 ⁺ stem cell activation and hair follicle regeneration through TNF

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.

Abstract

Hair can be regenerated after skin wounding. Here the authors show that inflammatory macrophages produce TNF that activates Wnt signalling in hair follicle stem cells to drive this hair regeneration after wound repair in mice.