@article{9b552bd1d74b46dd8ea64912aed7c62b,
title = "Dedifferentiation maintains melanocyte stem cells in a dynamic niche",
abstract = "For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4–8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.",
author = "Qi Sun and Wendy Lee and Hai Hu and Tatsuya Ogawa and {De Leon}, Sophie and Ioanna Katehis and Lim, {Chae Ho} and Makoto Takeo and Michael Cammer and Taketo, {M. Mark} and Gay, {Denise L.} and Millar, {Sarah E.} and Mayumi Ito",
note = "Funding Information: We thank V. Greco and P. Myung at Yale University who enabled us to examine melanocytes using in vivo imaging; P. Manga and S. J. Orlow for their help and support on pigmentation biology; staff at the NYU Langone{\textquoteright}s Microscope Laboratory for assistance with microscopy; S. Y. Kim at the Rodent Genetic Engineering Laboratory of NYU Langone for generating the Oca2 knock-in line; staff at the NYU Langone{\textquoteright}s Genome Technology Center for expert assistance with library preparation and Illumina sequencing; past and present members of the Ito Laboratory for their technical help and intellectual input; V. N. Nivsarkar and A. Brinks for help in formatting the manuscript; J. Walczyk for making the customized platform for in vivo imaging; and members of NYU Langone{\textquoteright}s Experimental Pathology Research Laboratory (RRID:SCR_017928), particularly S. Selvaraj and C. A. Loomis, for in situ hybridization. The cell sorting and flow cytometry technologies were provided by NYU Langone{\textquoteright}s Cytometry and Cell Sorting Laboratory. These centres are partially supported by a Cancer Center Support Grant (P30CA016087) at NYU Langone{\textquoteright}s Laura and Isaac Perlmutter Cancer Center and funds from the Shared Instrumentation Grant (S10 OD021747). M.I. appreciates support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (R01 AR059768, R01 AR074995 and U54CA263001-01A1), the Department of Defense (W81XWH2110435 and W81XWH-21-1-0510), and the Orbuch & Brand Pilot Grant Program for Diseases of the Skin. Q.S. was supported by a Melanoma Research Alliance Dermatology Fellows Award (654765 and 812413) and by a NYSTEM institutional training grant (contract C026880). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. creER Funding Information: We thank V. Greco and P. Myung at Yale University who enabled us to examine melanocytes using in vivo imaging; P. Manga and S. J. Orlow for their help and support on pigmentation biology; staff at the NYU Langone{\textquoteright}s Microscope Laboratory for assistance with microscopy; S. Y. Kim at the Rodent Genetic Engineering Laboratory of NYU Langone for generating the Oca2creERknock-in line; staff at the NYU Langone{\textquoteright}s Genome Technology Center for expert assistance with library preparation and Illumina sequencing; past and present members of the Ito Laboratory for their technical help and intellectual input; V. N. Nivsarkar and A. Brinks for help in formatting the manuscript; J. Walczyk for making the customized platform for in vivo imaging; and members of NYU Langone{\textquoteright}s Experimental Pathology Research Laboratory (RRID:SCR_017928), particularly S. Selvaraj and C. A. Loomis, for in situ hybridization. The cell sorting and flow cytometry technologies were provided by NYU Langone{\textquoteright}s Cytometry and Cell Sorting Laboratory. These centres are partially supported by a Cancer Center Support Grant (P30CA016087) at NYU Langone{\textquoteright}s Laura and Isaac Perlmutter Cancer Center and funds from the Shared Instrumentation Grant (S10 OD021747). M.I. appreciates support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (R01 AR059768, R01 AR074995 and U54CA263001-01A1), the Department of Defense (W81XWH2110435 and W81XWH-21-1-0510), and the Orbuch & Brand Pilot Grant Program for Diseases of the Skin. Q.S. was supported by a Melanoma Research Alliance Dermatology Fellows Award (654765 and 812413) and by a NYSTEM institutional training grant (contract C026880). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = apr,
day = "27",
doi = "10.1038/s41586-023-05960-6",
language = "English",
volume = "616",
pages = "774--782",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7958",
}