Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice

Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse...

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Published inDevelopmental cell Vol. 58; no. 24; pp. 2914 - 2929.e7
Main Authors Funk, Maja C, Gleixner, Jan G, Heigwer, Florian, Vonficht, Dominik, Valentini, Erica, Aydin, Zeynep, Tonin, Elena, Del Prete, Stefania, Mahara, Sylvia, Throm, Yannick, Hetzer, Jenny, Heide, Danijela, Stegle, Oliver, Odom, Duncan T, Feldmann, Angelika, Haas, Simon, Heikenwalder, Mathias, Boutros, Michael
Format Journal Article
LanguageEnglish
Published United States 18.12.2023
Subjects
Animals
Inflammation
Intestinal Mucosa
Intestines
Mice
Phenotype
Stem Cells
ageing
inflammaging
intestine
inflammation
intestinal stem cells
ISC
intestinal epithelium
interferon
epigenetics
single-cell analysis
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Summary:Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.
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ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2023.11.013