1. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility.
- Author
-
Koester J, Miroshnikova YA, Ghatak S, Chacón-Martínez CA, Morgner J, Li X, Atanassov I, Altmüller J, Birk DE, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, and Wickström SA
- Subjects
- Animals, Cell Lineage, Cells, Cultured, Extracellular Matrix physiology, Gene Silencing, Hair Follicle cytology, Hair Follicle metabolism, Male, Mechanotransduction, Cellular, Mice, Inbred C57BL, Mice, Knockout, Skin Aging, Stem Cells metabolism, Stress, Mechanical, Transcription, Genetic, Mice, Cell Differentiation genetics, Cell Self Renewal genetics, Cellular Senescence genetics, Chromatin Assembly and Disassembly, Hair Follicle physiology, Promoter Regions, Genetic, Stem Cell Niche, Stem Cells physiology
- 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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
- Full Text
- View/download PDF