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.