Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility.
Animals
Cell Differentiation
/ genetics
Cell Lineage
Cell Self Renewal
/ genetics
Cells, Cultured
Cellular Senescence
/ genetics
Chromatin Assembly and Disassembly
Extracellular Matrix
/ physiology
Gene Silencing
Hair Follicle
/ cytology
Male
Mechanotransduction, Cellular
Mice, Inbred C57BL
Mice, Knockout
Promoter Regions, Genetic
Skin Aging
Stem Cell Niche
Stem Cells
/ metabolism
Stress, Mechanical
Transcription, Genetic
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
06
04
2020
accepted:
27
05
2021
pubmed:
10
7
2021
medline:
21
9
2021
entrez:
9
7
2021
Statut:
ppublish
Résumé
Tissue turnover requires activation and lineage commitment of tissue-resident stem cells (SCs). These processes are impacted by ageing, but the mechanisms remain unclear. Here, we addressed the mechanisms of ageing in murine hair follicle SCs (HFSCs) and observed a widespread reduction in chromatin accessibility in aged HFSCs, particularly at key self-renewal and differentiation genes, characterized by bivalent promoters occupied by active and repressive chromatin marks. Consistent with this, aged HFSCs showed reduced ability to activate bivalent genes for efficient self-renewal and differentiation. These defects were niche dependent as the transplantation of aged HFSCs into young recipients or synthetic niches restored SC functions. Mechanistically, the aged HFSC niche displayed widespread alterations in extracellular matrix composition and mechanics, resulting in mechanical stress and concomitant transcriptional repression to silence promoters. As a consequence, increasing basement membrane stiffness recapitulated age-related SC changes. These data identify niche mechanics as a central regulator of chromatin state, which, when altered, leads to age-dependent SC exhaustion.
Identifiants
pubmed: 34239060
doi: 10.1038/s41556-021-00705-x
pii: 10.1038/s41556-021-00705-x
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
771-781Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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