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Nature cell biology
07, 2021;23 (7): 771-781.

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
Author Information
  1. Janis Koester: Max Planck Institute for Biology of Ageing, Cologne, Germany. ORCID
  2. Yekaterina A Miroshnikova: Max Planck Institute for Biology of Ageing, Cologne, Germany.
  3. Sushmita Ghatak: Max Planck Institute for Biology of Ageing, Cologne, Germany.
  4. Carlos Andrés Chacón-Martínez: Max Planck Institute for Biology of Ageing, Cologne, Germany.
  5. Jessica Morgner: Max Planck Institute for Biology of Ageing, Cologne, Germany. ORCID
  6. Xinping Li: Max Planck Institute for Biology of Ageing, Cologne, Germany. ORCID
  7. Ilian Atanassov: Max Planck Institute for Biology of Ageing, Cologne, Germany. ORCID
  8. Janine Altmüller: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  9. David E Birk: Department of Molecular Pharmacology & Physiology, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
  10. Manuel Koch: Institute for Dental Research and Oral Musculoskeletal Research, Center for Biochemistry, University of Cologne, Cologne, Germany. ORCID
  11. Wilhelm Bloch: Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany.
  12. Michaela Bartusel: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. ORCID
  13. Carien M Niessen: Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne, Cologne, Germany.
  14. Alvaro Rada-Iglesias: Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne, Cologne, Germany. ORCID
  15. Sara A Wickström: Max Planck Institute for Biology of Ageing, Cologne, Germany. sara.wickstrom@helsinki.fi. ORCID
PMID: 34239060 DOI: 10.1038/s41556-021-00705-x

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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MeSH Term

Animals
Cell Differentiation
Cell Lineage
Cell Self Renewal
Cells, Cultured
Cellular Senescence
Chromatin Assembly and Disassembly
Extracellular Matrix
Gene Silencing
Hair Follicle
Male
Mechanotransduction, Cellular
Mice, Inbred C57BL
Mice, Knockout
Promoter Regions, Genetic
Skin Aging
Stem Cell Niche
Stem Cells
Stress, Mechanical
Transcription, Genetic
Mice
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 126

Word Cloud

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