Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche.Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice.On single-cell RNA-sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5a high states.Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18 and Zfp239.These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair growth-related pathways.Among these is non-conventional TGFβ ligand Scube3.We show that in normal mouse skin Scube3 is expressed only in dermal papillae of growing, but not resting follicles.SCUBE3 protein microinjection is sufficient to induce new hair growth and pharmacological TGFβ inhibition rescues mutant hair hyper-activation phenotype.Moreover, dermal papilla-enriched expression of SCUBE3 and its growth activating effect are partially conserved in human scalp hair follicles.Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGFβ mechanism.