Signalling by senescent melanocytes hyperactivates hair growth

• Published in: Nature (London) Vol. 618; no. 7966; pp. 808 - 817
• Main Authors: Wang, Xiaojie, Ramos, Raul, Phan, Anne Q., Yamaga, Kosuke, Flesher, Jessica L., Jiang, Shan, Oh, Ji Won, Jin, Suoqin, Jahid, Sohail, Kuan, Chen-Hsiang, Nguyen, Truman Kt, Liang, Heidi Y., Shettigar, Nitish Udupi, Hou, Renzhi, Tran, Kevin H., Nguyen, Andrew, Vu, Kimberly N., Phung, Jennie L., Ingal, Jonard P., Levitt, Katelyn M., Cao, Xiaoling, Liu, Yingzi, Deng, Zhili, Taguchi, Nobuhiko, Scarfone, Vanessa M., Wang, Guangfang, Paolilli, Kara Nicole, Wang, Xiaoyang, Guerrero-Juarez, Christian F., Davis, Ryan T., Greenberg, Elyse Noelani, Ruiz-Vega, Rolando, Vasudeva, Priya, Murad, Rabi, Widyastuti, Lily Halida Putri, Lee, Hye-Lim, McElwee, Kevin J., Gadeau, Alain-Pierre, Lawson, Devon A., Andersen, Bogi, Mortazavi, Ali, Yu, Zhengquan, Nie, Qing, Kunisada, Takahiro, Karin, Michael, Tuckermann, Jan, Esko, Jeffrey D., Ganesan, Anand K., Li, Ji, Plikus, Maksim V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2023; Nature Publishing Group
• Subjects: 13; 13/100; 13/31; 13/51; 14; 14/32; 38; 38/91; 631/532/2139; 631/532/2438; 631/80/509; 631/80/86/820; 64; 64/110; 64/60; 82; Albinism; Animal models; Animals; CD44 antigen; Clusters; Congenital diseases; Disorders; Follicles; Genotoxicity; Genotype & phenotype; Hair; Hair - cytology; Hair - growth & development; Hair cells; Hair Follicle - cytology; Hair Follicle - physiology; Human health and pathology; Humanities and Social Sciences; Hyaluronan Receptors - metabolism; Life Sciences; Melanocytes; Melanocytes - cytology; Melanocytes - metabolism; Mice; multidisciplinary; Mutation; Nevus; Nevus - metabolism; Nevus - pathology; Osteopontin; Osteopontin - metabolism; Science; Science (multidisciplinary); Secretome; Senescence; Signal Transduction; Signaling; Stem cells; Stem Cells - cytology; Therapeutic targets; Transcriptomes; Hair; Stem Cells; Animals; Signal Transduction; Article recherche; Hair Follicle; Hyaluronan Receptors; Nevus; Osteopontin; Melanocytes; Mice
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06172-8

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration 1 . 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 nevi 2 , 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 tissue 4 , 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. Senescent melanocytes of skin nevi drive hyperactivation of hair growth through the signalling factor SPP1.