TGFα is required for hair follicle function during aging and its loss leads to progressive alopecia

The contributions of specific growth factors (GFs) to hair follicle maintenance during aging remain poorly understood. The GF TGFα affects postnatal hair morphogenesis, and its loss leads to wavy hairs in young mice. Whether TGFα is required for proper hair follicle function during aging has not been explored. In this study, we find that loss of TGFα results in severe progressive alopecia, leading to an almost complete absence of back hairs in aged mice. Deep hair phenomics shows that the progressive hair loss is associated with a switch of hair-type proportions toward zigzag hairs, increased hair waviness, decreased hair length, and increased trichoptilosis with multiple hair breakage points. Hair loss is associated with a progressive dilatation of the upper hair follicle, which showed keratinocyte differentiation abnormalities. Metabolomic analyses of epidermal sheets identified diminished levels of prostaglandin H2 in Tgfa^-/- mice. Transcriptomic analyses linked the hair loss in aged Tgfa^-/- mice to upregulation of genes involved in retinyl ester synthesis in keratinocytes, which resulted in increased retinyl stearate in skin of aged Tgfa^-/- mice. Collectively, these findings identify TGFα as a critical regulator of hair follicles during aging, whose loss leads to progressive alopecia, associated with dysregulation of prostaglandin and retinoid metabolism.