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Although patches of white hair on the scalp (poliosis) are considered as early signs of TS, the underlying molecular mechanisms and potential involvement of mTORC1 in hair depigmentation remain unclear. Here, we have used healthy, organ\u2010cultured human scalp hair follicles (HFs) to interrogate the role of mTORC1 in a prototypic human (mini\u2010)organ. Gray\/white HFs exhibit high mTORC1 activity, while mTORC1 inhibition by rapamycin stimulated HF growth and pigmentation, even in gray\/white HFs that still contained some surviving melanocytes. Mechanistically, this occurred via increased intrafollicular production of the melanotropic hormone, \u03b1\u2010MSH. In contrast, knockdown of intrafollicular TSC2, a negative regulator of mTORC1, significantly reduced HF pigmentation. Our findings introduce mTORC1 activity as an important negative regulator of human HF growth and pigmentation and suggest that pharmacological mTORC1 inhibition could become a novel strategy in the management of hair loss and depigmentation disorders.<\/jats:p>","DOI":"10.15252\/embr.202256574","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T04:15:21Z","timestamp":1684728921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["mTORC1 activity negatively regulates human hair follicle growth and pigmentation"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6012-0229","authenticated-orcid":false,"given":"Takahiro","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1901-0551","authenticated-orcid":false,"given":"J\u00e9r\u00e9my","family":"Ch\u00e9ret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Dinelli","family":"Scala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysun","family":"Akhundlu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4811-8580","authenticated-orcid":false,"given":"Jennifer","family":"Gherardini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana\u2010Lee","family":"Demetrius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D B","family":"O'Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gorana","family":"Kuka Epstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-1270","authenticated-orcid":false,"given":"Alan J","family":"Bauman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7813-7726","authenticated-orcid":false,"given":"Constantinos","family":"Demetriades","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-9358","authenticated-orcid":false,"given":"Ralf","family":"Paus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"BFEMBR202256574_CR1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1111\/j.1525-1470.2008.00731.x","volume":"25","author":"Y Apibal","year":"2008","unstructured":"Apibal Y, Reakatanan W, Chunharas A (2008) Poliosis as the first clue of tuberous sclerosis. 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For the record, RP and JC and JG were or are employees of Monasterium Laboratory, a skin & hair research CRO (\n                      \n                      ) that provides HF research services, and RP has founded and JC consults for a company (\n                      \n                      ) that develops hair growth\/pigmentation\u2010modulatory treatment strategies.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}],"article-number":"EMBR202256574"}}