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

doi:10.1016/j.devcel.2022.06.005

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

Dev Cell. 2022 Jul 25;57(14):1758-1775.e7. doi: 10.1016/j.devcel.2022.06.005. Epub 2022 Jun 30.

Authors

Yingzi Liu¹, Christian F Guerrero-Juarez², Fei Xiao³, Nitish Udupi Shettigar⁴, Raul Ramos⁵, Chen-Hsiang Kuan⁶, Yuh-Charn Lin⁷, Luis de Jesus Martinez Lomeli⁸, Jung Min Park⁹, Ji Won Oh¹⁰, Ruiqi Liu¹¹, Sung-Jan Lin¹², Marco Tartaglia¹³, Ruey-Bing Yang¹⁴, Zhengquan Yu¹¹, Qing Nie¹⁵, Ji Li¹⁶, Maksim V Plikus¹⁷

Affiliations

¹ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
² Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
³ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Amplifica Holdings Group, Inc., San Diego, CA 92128, USA.
⁵ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁸ Department of Statistics, University of California, Irvine, Irvine, CA 92697, USA.
⁹ Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea; Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Korea.
¹⁰ Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea; Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Korea; Hair Transplantation Center, Kyungpook National University Hospital, Daegu, Korea.
¹¹ State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
¹² Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Engineering and Department of Dermatology, National Taiwan University, Taipei, Taiwan.
¹³ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
¹⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
¹⁵ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
¹⁶ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: liji_xy@csu.edu.cn.
¹⁷ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: plikus@uci.edu.

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 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.

Keywords: Hedgehog pathway; Leptin receptor; Scube3; dermal papilla; fibroblasts; hair follicle; hair growth; stem cell niche.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Binding Proteins / metabolism
Cells, Cultured
Fibroblasts / metabolism
Hair
Hair Follicle* / metabolism
Hedgehog Proteins* / metabolism
Humans
Mice
SOXF Transcription Factors / metabolism
Transforming Growth Factor beta / metabolism

Substances

Calcium-Binding Proteins
Hedgehog Proteins
SCUBE3 protein, human
SOX18 protein, human
SOXF Transcription Factors
Transforming Growth Factor beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding