Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF- axis

In aging, androgenic alopecia, and genetic hypotrichosis disorders, hair shaft miniaturization is often associated with hair follicle stem cell (HFSC) loss. However, the mechanism causing this stem cell depletion in vivo remains elusive. Here we show that hair shaft loss or a reduction in diameter shrinks the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss. Mechanistically, cell compression activates the mechanosensitive channel Piezo1, which triggers calcium influx. This confers tumor necrosis factor alpha (TNF-alpha) sensitivity in a hair-cycle-dependent manner in otherwise resistant HFSCs and induces ectopic apoptosis. Persistent hair shaft miniaturization during aging and genetic hypotrichosis disorders causes long-term HFSC loss by inducing continuous ectopic apoptosis through Piezo1. Our results identify an unconventional role of the inert hair shaft structure as a functional niche component governing HFSC survival and reveal a mechanosensory axis that regulates physical-niche-atrophy-induced stem cell depletion in vivo.