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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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Main Authors: Funk, Maja C. (Author) , Gleixner, Jan G. (Author) , Heigwer, Florian (Author) , Vonficht, Dominik (Author) , Valentini, Erica (Author) , Aydin, Zeynep (Author) , Tonin, Elena (Author) , Del Prete, Stefania (Author) , Mahara, Sylvia (Author) , Throm, Yannick (Author) , Hetzer, Jenny (Author) , Heide, Danijela (Author) , Stegle, Oliver (Author) , Odom, Duncan T. (Author) , Feldmann, Angelika (Author) , Haas, Simon (Author) , Heikenwälder, Mathias (Author) , Boutros, Michael (Author)
Format: Article (Journal)
Language:English
Published: 18 December 2023
In: Developmental cell
Year: 2023, Volume: 58, Issue: 24, Pages: 2914-2929
ISSN:1878-1551
DOI:10.1016/j.devcel.2023.11.013
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.devcel.2023.11.013
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1534580723006111
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Author Notes:Maja C. Funk, Jan G. Gleixner, Florian Heigwer, Dominik Vonficht, Erica Valentini, Zeynep Aydin, Elena Tonin, Stefania Del Prete, Sylvia Mahara, Yannick Throm, Jenny Hetzer, Danijela Heide, Oliver Stegle, Duncan T. Odom, Angelika Feldmann, Simon Haas, Mathias Heikenwalder, and Michael Boutros
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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.
Item Description:Online verfügbar: 18. Dezember 2023, Artikelversion: 18. Dezember 2023
Gesehen am 08.04.2024
Physical Description:Online Resource
ISSN:1878-1551
DOI:10.1016/j.devcel.2023.11.013

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