Gasdermin A3-Mediated Cell Death Causes Niche Collapse and Precocious Activation of Hair Follicle Stem Cells.

Hair follicles undergo recurrent growth, regression, and resting phases throughout postnatal life, which is supported by hair follicle stem cells. The niche components of hair follicle stem cells are important to maintain their quiescence and stemness. Gsdma3 gain-of-function mutations in mice cause chronic skin inflammation, aberrant hair cycle, and progressive hair loss, reminiscent of scarring alopecia in humans. However, the mechanism underlying these defects remains elusive. Here, we used a combined Cre/loxP and rtTA/TRE system to study the spatiotemporal effect of Gsdma3 overexpression on distinct hair cycle stages. We found that Gsdma3-mediated cell death affects anagen initiation, anagen progression, and catagen-telogen transition. Induced Gsdma3 expression causes bulge inner layer collapse and precocious hair follicle stem cell activation, leading to subsequent hair follicle degeneration. Although macrophages and dendritic cells are recruited to the bulge region, in vivo depletion of these cells using a neutralizing antibody does not alleviate cell death in the bulge or hair germ, indicating that macrophages are less likely to cause immediate hair follicle deletion. Our data suggest that dysregulated Gsdma3 causes bulge inner layer necrosis to induce club hair shedding and immediate anagen reentry without going through telogen morphology, which implicates a role for Gsdma3 in hair follicle stem cell niche maintenance.

Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling.

Adult hair follicles undergo repeated cycling of regression (catagen), resting (telogen), and growth (anagen), which is maintained by hair follicle stem cells (HFSCs). The mechanism underlying hair growth initiation and HFSC maintenance is not fully understood. Here, by epithelial deletion of Hes1, a major Notch downstream transcriptional repressor, we found that hair growth is retarded, but the hair cycle progresses normally. Hes1 is specifically upregulated in the lower bulge/HG during anagen initiation. Accordingly, loss of Hes1 results in delayed activation of the secondary hair germ (HG) and shortened anagen phase. This developmental delay causes reduced hair shaft length but not identity changes in follicular lineages. Remarkably, Hes1 ablation results in impaired hair regeneration upon repetitive depilation. Microarray gene profiling on HFSCs indicates that Hes1 modulates Shh responsiveness in anagen initiation. Using primary keratinocyte cultures, we demonstrated that Hes1 deletion negatively influences ciliogenesis and Smoothened ciliary accumulation upon Shh treatment. Furthermore, transient application of Smoothened agonist during repetitive depilation can rescue anagen initiation and HFSC self-renewal in Hes1-deficient hair follicles. We reveal a critical function of Hes1 in potentiating Shh signaling in anagen initiation, which allows sufficient signaling strength to expand the HG and replenish HFSCs to maintain the hair cycle homeostasis.