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

Janis Koester, Yekaterina A Miroshnikova, Sushmita Ghatak, Carlos Andrés Chacón-Martínez, Jessica Morgner, Xinping Li, Ilian Atanassov, Janine Altmüller, David E Birk, Manuel Koch, Wilhelm Bloch, Michaela Bartusel, Carien M Niessen, Alvaro Rada-Iglesias, Sara A Wickström*

*Corresponding author for this work

Publication: Contribution to journalJournal articlesResearchpeer-review

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.
Original languageEnglish
JournalNature cell biology
Volume23
Issue number7
Pages (from-to)771-781
Number of pages11
ISSN1465-7392
DOIs
Publication statusPublished - 08.07.2021

Research areas and keywords

  • 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

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