Signalling by senescent melanocytes hyperactivates hair growth

Xiaojie Wang (), Raul Ramos, Anne Q. Phan, Kosuke Yamaga, Jessica L. Flesher, Shan Jiang, Ji Won Oh, Suoqin Jin, Sohail Jahid, Chen-Hsiang Kuan, Truman Kt Nguyen, Heidi Y. Liang, Nitish Udupi Shettigar, Renzhi Hou, Kevin H. Tran, Andrew Nguyen, Kimberly N. Vu, Jennie L. Phung, Jonard P. Ingal, Katelyn M. Levitt, Xiaoling Cao, Yingzi Liu, Zhili Deng, Nobuhiko Taguchi, Vanessa M. Scarfone, Guangfang Wang, Kara Nicole Paolilli, Xiaoyang Wang, Christian F. Guerrero-Juarez, Ryan T. Davis, Elyse Noelani Greenberg, Rolando Ruiz-Vega, Priya Vasudeva, Rabi Murad, Lily Halida Putri Widyastuti, Hye-Lim Lee, Kevin J. McElwee, Alain-Pierre Gadeau, Devon A. Lawson, Bogi Andersen, Ali Mortazavi, Zhengquan Yu, Qing Nie, Takahiro Kunisada, Michael Karin, Jan Tuckermann, Jeffrey D. Esko, Anand K. Ganesan, Ji Li and Maksim V. Plikus ()
Additional contact information
Xiaojie Wang: University of California
Raul Ramos: University of California
Anne Q. Phan: University of California, San Diego
Kosuke Yamaga: University of California
Jessica L. Flesher: University of California
Shan Jiang: University of California
Ji Won Oh: Yonsei University College of Medicine
Suoqin Jin: University of California
Sohail Jahid: University of California
Chen-Hsiang Kuan: University of California
Truman Kt Nguyen: University of California
Heidi Y. Liang: University of California
Nitish Udupi Shettigar: University of California
Renzhi Hou: University of California
Kevin H. Tran: University of California
Andrew Nguyen: University of California
Kimberly N. Vu: University of California
Jennie L. Phung: University of California
Jonard P. Ingal: University of California
Katelyn M. Levitt: University of California
Xiaoling Cao: University of California
Yingzi Liu: University of California
Zhili Deng: Xiangya Hospital, Central South University
Nobuhiko Taguchi: Gifu University Graduate School of Medicine
Vanessa M. Scarfone: University of California
Guangfang Wang: University of California
Kara Nicole Paolilli: University of California
Xiaoyang Wang: University of California
Christian F. Guerrero-Juarez: University of California
Ryan T. Davis: University of California
Elyse Noelani Greenberg: University of California
Rolando Ruiz-Vega: University of California
Priya Vasudeva: University of California
Rabi Murad: University of California
Lily Halida Putri Widyastuti: University of California
Hye-Lim Lee: University of California
Kevin J. McElwee: University of Bradford
Alain-Pierre Gadeau: University of Bordeaux, INSERM U1034, Adaptation cardiovasculaire à l’ischémie
Devon A. Lawson: University of California
Bogi Andersen: University of California
Ali Mortazavi: University of California
Zhengquan Yu: China Agricultural University
Qing Nie: University of California
Takahiro Kunisada: Gifu University Graduate School of Medicine
Michael Karin: University of California San Diego, School of Medicine
Jan Tuckermann: University of Ulm, Helmholtzstrasse 8/1
Jeffrey D. Esko: University of California, San Diego
Anand K. Ganesan: University of California
Ji Li: Xiangya Hospital, Central South University
Maksim V. Plikus: University of California

Nature, 2023, vol. 618, issue 7966, 808-817

Abstract: Abstract Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Date: 2023
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DOI: 10.1038/s41586-023-06172-8

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