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PreprintCited by 60Genetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and SenescenceSingle-cell and spatial transcriptomics

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Epithelial cells of the intestine acquire cell-intrinsic inflammation signatures during ageing

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Funk, Maja C., Gleixner, Jan G., Heigwer, Florian, Valentini, Erica, Aydin, Zeynep, Tonin, Elena, Hetzer, Jenny, Heide, Danijela, Stegle, Oliver, Heikenwalder, Mathias, Boutros, Michael·2021·Developmental Cell
DOI 10.1101/2021.12.19.473357

Preprint — published as 10.1016/j.devcel.2023.11.013

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Abstract

During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

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Metadata

Authors
Funk, M. C., Gleixner, J. G., Heigwer, F., Valentini, E., Aydin, Z., Tonin, E., Hetzer, J., Heide, D., Stegle, O., Heikenwalder, M., & Boutros, M.
Affiliations
  • German Cancer Research Center (DE)
  • TH Bingen University of Applied Sciences (DE)
Corresponding author
Boutros, Michael
ORCID
Venue
Developmental Cell
Publisher
openRxiv
Published
2021-12-19
Volume
58
Issue
24
Pages
2914-2929.e7
ISSN
1534-5807 (ISSN-L)
DOI
10.1101/2021.12.19.473357
OpenAlex
W4389917091
Cited by
60
References
1
Citations by year
2026: 22 · 2025: 29 · 2024: 9
FWCI
4.05
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Developmental Cell (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Funders
  • Deutsches Krebsforschungszentrum
  • Helmholtz Association
  • European Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
inflammaging, intestinal stem cells, aging, low-grade inflammation, MHC class II, STAT1 signaling, chromatin accessibility, intestinal organoids, crypt-villus axis, immune homeostasis, single-cell transcriptomics
MeSH terms
Animals, Inflammation, Intestinal Mucosa, Intestines, Phenotype, Stem Cells, Mice

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