Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility
Abstract
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.
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The ageing skin is characterized by niche stiffening and hair shaft miniaturization, which are accompanied by defects in hair follicle stem cells (HFSCs).
“The ageing skin is characterized by niche stiffening and hair shaft miniaturization, which are accompanied by defects in hair follicle stem cells (HFSCs)83,84.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [84]
In HFSCs, ageing is associated with decreased chromatin accessibility, notably silencing of bivalent promoters.
“For example, in HFSCs, ageing is associated with decreased chromatin accessibility, notably silencing of ‘bivalent’ promoters (that is, marked by both H3K27me3 and H3K4me3)84.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [84]
These age-dependent chromatin changes in HFSCs are affected by stiffening of the niche and could mediate the impact of external and biophysical properties on stem cells during ageing.
“These age-dependent chromatin changes in HFSCs are affected by stiffening of the niche84, and could mediate the impact of external and biophysical properties on stem cells during ageing.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [84]
In the skin, niche stiffening and persistent hair shaft miniaturization during ageing can contribute to HFSC ageing via a reduction in promoter bivalency in HFSCs and via a PIEZO1-TNF mechanism.
“In the skin, niche stiffening and persistent hair shaft miniaturization during ageing can also contribute to HFSC ageing via a reduction in promoter bivalency in HFSCs84 and via a PIEZO1–TNF mechanism83.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [84]
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Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
- Authors
- Koester, J., Miroshnikova, Y. A., Ghatak, S., Chacón-Martínez, C. A., Morgner, J., Li, X., Atanassov, I., Altmüller, J., Birk, D. E., Koch, M., Bloch, W., Bartusel, M., Niessen, C. M., Rada-Iglesias, A., & Wickström, S. A.
- Affiliations
- University of Cologne (DE)
- University of Helsinki (FI)
- Max Planck Institute for Biology of Ageing (DE)
- University of South Florida (US)
- German Sport University Cologne (DE)
- Corresponding author
- Wickström, Sara A.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2021-07
- Volume
- 23
- Issue
- 7
- Pages
- 771-781
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W3183123849
- Cited by
- 117
- References
- 53
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 23 · 2023: 19 · 2022: 22 · 2021: 1
- FWCI
- 18.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- hair follicle stem cells, aging, chromatin accessibility, bivalent promoters, extracellular matrix mechanics, stem cell self-renewal, stem cell differentiation, transcriptional repression, tissue turnover
- MeSH terms
- Cell Self Renewal, Animals, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Stem Cells, Stress, Mechanical, Transcription, Genetic, Skin Aging, Cellular Senescence, Mice, Knockout, Hair Follicle, Cell Lineage, Gene Silencing, Mechanotransduction, Cellular, Chromatin Assembly and Disassembly, Mice, Stem Cell Niche
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