Developmental cell · 2022

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

Liu, Y. and Guerrero-Juarez, C. F. and Xiao, F. and Shettigar, N. U. and Ramos, R. and Kuan, C. and Lin, Y. and de Jesus Martinez Lomeli, L. and Park, J. M. and Oh, J. W. and Liu, R. and Lin, S. and Tartaglia, M. and Yang, R. and Yu, Z. and Nie, Q. and Li, J. and Plikus, M. V.

doi:10.1016/j.devcel.2022.06.005

Abstract

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 Wnt5ahigh 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.

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Developmental cell 2022

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

Liu, Y. and Guerrero-Juarez, C. F. and Xiao, F. and Shettigar, N. U. and Ramos, R. and Kuan, C. and Lin, Y. and de Jesus Martinez Lomeli, L. and Park, J. M. and Oh, J. W. and Liu, R. and Lin, S. and Tartaglia, M. and Yang, R. and Yu, Z. and Nie, Q. and Li, J. and Plikus, M. V.

doi:10.1016/j.devcel.2022.06.005

Abstract

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 Wnt5ahigh 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.

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Central South University Xiangya Hospital Li Lab Skin Aging and Hair Regeneration Research Center