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.

毛囊干细胞受到真皮乳头成纤维细胞的调节，这是它们的主要信号传导生态位。生态位中 Hedgehog 信号的过度激活会显着加速小鼠的毛发生长并诱导毛囊增殖。在单细胞 RNA 测序中，真皮乳头成纤维细胞增加了异质性，包括新的Wnt5a^高状态。在转录方面，突变的成纤维细胞激活 Gli1、Alx3、Ebf1、Hoxc8、Sox18 和 Zfp239 的调控网络。这些网络共同上调多种毛发形态发生和毛发生长相关途径的分泌因子。其中包括非传统的 TGF-β 配体Scube3。我们发现，在正常小鼠皮肤中，Scube3仅在生长的真皮乳头中表达，而不在静止的毛囊中表达。SCUBE3 蛋白显微注射足以诱导新毛发生长，药理学 TGF-β 抑制可挽救突变毛发过度激活表型。此外， SCUBE3在真皮乳头中的富集表达及其生长激活作用在人头皮毛囊中部分保留。因此，Hedgehog 通过 SCUBE3/TGF-β 机制调节毛囊中的间充质生态位功能。