TY - JOUR
T1 - The aging skin microenvironment dictates stem cell behavior
AU - Ge, Yejing
AU - Miao, Yuxuan
AU - Gur-Cohen, Shiri
AU - Gomez, Nicholas
AU - Yang, Hanseul
AU - Nikolova, Maria
AU - Polak, Lisa
AU - Hu, Yang
AU - Verma, Akanksha
AU - Elemento, Olivier
AU - Krueger, James G.
AU - Fuchs, Elaine
N1 - Funding Information:
We thank the The Rockefeller University flow cytometry resource center (Svetlana Mazel, director), genomics resource center (Connie Zhao, director) and microscopy resource center (Alison North, director) and the American Association for the Accreditation of Laboratory Animal Care-accredited comparative biology center (R. Tolwani, director) for their services; K.L., L.L., K.S., J.R., E.W., M.S., and J.L. for technical assistance; and S.E., R.A., M.L. and S.L. for critical comments and discussions. Y.G. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, The Irene Diamond Fund/American Federation for Aging Research Postdoctoral Transition Awards in Aging, Cancer Prevention and Research Institute of Texas first-time recruitment award. E.F. is an HHMI investigator. This work was funded by the Glenn Foundation (E.F.), National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01-AR050452 (to E.F.), American Federation for Aging Research (Y.G.), Career Development Award 1K01AR072132-01A1 (to Y.G.), and Cancer Prevention and Research Institute of Texas Recruitment Award FP00006955 (to Y.G.).
Funding Information:
ACKNOWLEDGMENTS. We thank the The Rockefeller University flow cytometry resource center (Svetlana Mazel, director), genomics resource center (Connie Zhao, director) and microscopy resource center (Alison North, director) and the American Association for the Accreditation of Laboratory Animal Care-accredited comparative biology center (R. Tolwani, director) for their services; K.L., L.L., K.S., J.R., E.W., M.S., and J.L. for technical assistance; and S.E., R.A., M.L. and S.L. for critical comments and discussions. Y.G. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, The Irene Diamond Fund/American Federation for Aging Research Postdoctoral Transition Awards in Aging, Cancer Prevention and Research Institute of Texas first-time recruitment award. E.F. is an HHMI investigator. This work was funded by the Glenn Foundation (E.F.), National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01-AR050452 (to E.F.), American Federation for Aging Research (Y.G.), Career Development Award 1K01AR072132-01A1 (to Y.G.), and Cancer Prevention and Research Institute of Texas Recruitment Award FP00006955 (to Y.G.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/3/10
Y1 - 2020/3/10
N2 - Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
AB - Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
KW - Aging
KW - Hair follicle
KW - Lineage identity
KW - Skin
KW - Stem cells
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U2 - 10.1073/pnas.1901720117
DO - 10.1073/pnas.1901720117
M3 - Article
C2 - 32094197
AN - SCOPUS:85081652492
SN - 0027-8424
VL - 117
SP - 5339
EP - 5350
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -