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

Yingzi Liu, Christian F. Guerrero-Juarez, Fei Xiao, Nitish Udupi Shettigar, Raul Ramos, Chen Hsiang Kuan, Yuh Charn Lin, Luis de Jesus Martinez Lomeli, Jung Min Park, Ji Won Oh, Ruiqi Liu, Sung Jan Lin, Marco Tartaglia, Ruey Bing Yang, Zhengquan Yu, Qing Nie, Ji Li, Maksim V. Plikus

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1758-1775.e7
JournalDevelopmental Cell
Volume57
Issue number14
DOIs
Publication statusPublished - Jul 25 2022

Keywords

  • dermal papilla
  • fibroblasts
  • hair follicle
  • hair growth
  • Hedgehog pathway
  • Leptin receptor
  • Scube3
  • stem cell niche

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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