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Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility

Item Type:Article
Title:Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility
Creators Name:Koester, J. and Miroshnikova, Y.A. and Ghatak, S. and Chacón-Martínez, C.A. and Morgner, J. and Li, X. and Atanassov, I. and Altmüller, J. and Birk, D.E. and Koch, M. and Bloch, W. and Bartusel, M. and Niessen, C.M. and Rada-Iglesias, A. and Wickström, S.A.
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.
Keywords:Cell Differentiation, Cell Lineage, Cell Self Renewal, Cellular Mechanotransduction, Cellular Senescence, Chromatin Assembly and Disassembly, Cultured Cells, Extracellular Matrix, Gene Silencing, Genetic Promoter Regions, Genetic Transcription, Hair Follicle, Inbred C57BL Mice, Knockout Mice, Mechanical Stress, Skin Aging, Stem Cell Niche, Stem Cells, Animals, Mice
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:771-781
Date:July 2021
Official Publication:https://doi.org/10.1038/s41556-021-00705-x
PubMed:View item in PubMed

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