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IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration

Author

Listed:
  • Omid Omrani

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Anna Krepelova

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)
    University of Turin
    University of Turin)

  • Seyed Mohammad Mahdi Rasa

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Dovydas Sirvinskas

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Jing Lu

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Francesco Annunziata

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • George Garside

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Seerat Bajwa

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Susanne Reinhardt

    (Dresden-concept Genome Center, c/o Center for Regenerative Therapies Dresden (CRTD))

  • Lisa Adam

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Sandra Käppel

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Nadia Ducano

    (University of Turin
    University of Turin)

  • Daniela Donna

    (University of Turin
    University of Turin)

  • Alessandro Ori

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Salvatore Oliviero

    (University of Turin
    University of Turin)

  • Karl Lenhard Rudolph

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Francesco Neri

    (Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)
    University of Turin
    University of Turin)

Abstract

The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium.

Suggested Citation

  • Omid Omrani & Anna Krepelova & Seyed Mohammad Mahdi Rasa & Dovydas Sirvinskas & Jing Lu & Francesco Annunziata & George Garside & Seerat Bajwa & Susanne Reinhardt & Lisa Adam & Sandra Käppel & Nadia D, 2023. "IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41683-y
    DOI: 10.1038/s41467-023-41683-y
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