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Signalling by senescent melanocytes hyperactivates hair growth.

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 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 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC10284692 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Signalling by senescent melanocytes hyperactivates hair growth.

Wang Xiaojie X Ramos Raul R Phan Anne Q AQ Yamaga Kosuke K Flesher Jessica L JL Jiang Shan S Oh Ji Won JW Jin Suoqin S Jahid Sohail S Kuan Chen-Hsiang CH Nguyen Truman Kt TK Liang Heidi Y HY Shettigar Nitish Udupi NU Hou Renzhi R Tran Kevin H KH Nguyen Andrew A Vu Kimberly N KN Phung Jennie L JL Ingal Jonard P JP Levitt Katelyn M KM Cao Xiaoling X Liu Yingzi Y Deng Zhili Z Taguchi Nobuhiko N Scarfone Vanessa M VM Wang Guangfang G Paolilli Kara Nicole KN Wang Xiaoyang X Guerrero-Juarez Christian F CF Davis Ryan T RT Greenberg Elyse Noelani EN Ruiz-Vega Rolando R Vasudeva Priya P Murad Rabi R Widyastuti Lily Halida Putri LHP Lee Hye-Lim HL McElwee Kevin J KJ Gadeau Alain-Pierre AP Lawson Devon A DA Andersen Bogi B Mortazavi Ali A Yu Zhengquan Z Nie Qing Q Kunisada Takahiro T Karin Michael M Tuckermann Jan J Esko Jeffrey D JD Ganesan Anand K AK Li Ji J Plikus Maksim V MV

Nature 20230621 7966

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration<sup>1</sup>. 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<sup>2,3</sup>, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome a ...[more]

PMID: 37344645

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Project description:Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key factor involved. In this study, we examined the follicular melanin unit in variably pigmented follicles from the aging human scalp of healthy individuals (22-70 years). Over 20 markers were selected within the following categories: melanocyte-specific, apoptosis, cell cycle, DNA repair/damage, senescence and oxidative stress. As expected, a reduction in melanocyte-specific markers in proportion to the extent of canities was observed. A major finding of our study was the intense and highly specific nuclear expression of Ataxia Telangiectasia Mutated (ATM) protein within melanocytes in anagen hair follicle bulbs. ATM is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks and functions as an important sensor of reactive oxygen species (ROS) in human cells. The incidence and expression level of ATM correlated with pigmentary status in canities-affected hair follicles. Moreover, increased staining of the redox-associated markers 8-OHdG, GADD45 and GP-1 were also detected within isolated bulbar melanocytes, although this change was not clearly associated with donor age or canities extent. Surprisingly, we were unable to detect any specific change in the expression of other markers of oxidative stress, senescence or DNA damage/repair in the canities-affected melanocytes compared to surrounding bulbar keratinocytes. By contrast, several markers showed distinct expression of markers for oxidative stress and apoptosis/differentiation in the inner root sheath (IRS) as well as other parts of the hair follicle. Using our in vitro model of primary human scalp hair follicle melanocytes, we showed that ATM expression increased after incubation with the pro-oxidant hydrogen peroxide (H2O2). In addition, this ATM increase was prevented by pre-incubation of cells with antioxidants. The relationship between ATM and redox stress sensing was further evidenced as we observed that the inhibition of ATM expression by chemical inhibition promoted the loss of melanocyte viability induced by oxidative stress. Taken together these new findings illustrate the key role of ATM in the protection of human hair follicle melanocytes from oxidative stress/damage within the human scalp hair bulb. In conclusion, these results highlight the remarkable complexity and role of redox sensing in the status of human hair follicle growth, differentiation and pigmentation.

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Signalling by senescent melanocytes hyperactivates hair growth.

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Signalling by senescent melanocytes hyperactivates hair growth.

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