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 TGF-β ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-β 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/TGF-β mechanism. [Display omitted] • Hedgehog signaling in murine fibroblasts induces new hair growth and hair multiplication • Hedgehog activation increases fibroblast heterogeneity and drives new cell states • TGF-β pathway downstream of dermal Hedgehog mediates hair growth hyper-activation • SCUBE3 is a new mesenchymal niche factor that activates hair growth Liu and Guerrero-Juarez et al. demonstrate that genetic tools based on the leptin receptor gene Lepr can efficiently target hair follicle niche fibroblasts, called dermal papilla cells. Transgenic stimulation of the Hedgehog pathway in murine dermal papilla cells results in overactivation of hair growth via a downstream SCUBE3-TGF-β signaling mechanism. [ABSTRACT FROM AUTHOR]