Hedgehog Signaling Reprograms Hair Follicle Niche Fibroblasts to a Hyper-Activated State

The study demonstrates that overactivation of Hedgehog signaling in dermal papilla fibroblasts significantly accelerates hair growth and induces follicle multiplication in mice. Single-cell RNA sequencing revealed increased heterogeneity in these fibroblasts, including new Wnt5ahigh states. Mutant fibroblasts activated regulatory networks involving Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239, which upregulated secreted factors for hair morphogenesis and growth. Notably, the non-conventional TGF-β ligand SCUBE3 was identified as a key factor, expressed in growing but not resting follicles. SCUBE3 protein microinjection induced new hair growth, and TGF-β inhibition rescued the hyper-activation phenotype. SCUBE3's expression and growth-activating effects were partially conserved in human scalp hair follicles, indicating Hedgehog's role in regulating hair follicle mesenchymal niche function via the SCUBE3/TGF-β mechanism.