Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-α 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-α) 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. [Display omitted] •Hair shaft is a functional niche component directly regulating HFSC survival•Shrinkage of physical niche size causes HFSC loss by Piezo1-calcium-TNF-α signaling•In aged skin, mechanically compressed HFSCs undergo calcium-dependent apoptosis•Pathological hair shaft miniaturization causes long-term HFSC loss through Piezo1 Xie et al. demonstrate that hair shaft loss or a diameter decrease causes shrinkage of the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss in aging and disease. Piezo1 triggers calcium influx, causing sensitivity to TNF-α in otherwise resistant HFSCs to induce ectopic apoptosis.