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| Item Type: | Article |
|---|---|
| Title: | Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice |
| Creators Name: | Funk, M.C. and Gleixner, J.G. and Heigwer, F. and Vonficht, D. and Valentini, E. and Aydin, Z. and Tonin, E. and Del Prete, S. and Mahara, S. and Throm, Y. and Hetzer, J. and Heide, D. and Stegle, O. and Odom, D.T. and Feldmann, A. and Haas, S. and Heikenwalder, M. and Boutros, M. |
| Abstract: | 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. |
| Keywords: | Ageing, Inflammaging, ISC, Intestine, Single-Cell Analysis, Inflammation, Intestinal Stem Cells, Intestinal Epithelium, Interferon, Epigenetics, Animals, Mice |
| Source: | Developmental Cell |
| ISSN: | 1534-5807 |
| Publisher: | Cell Press |
| Volume: | 58 |
| Number: | 24 |
| Page Range: | 2914-2929 |
| Date: | 18 December 2023 |
| Official Publication: | https://doi.org/10.1016/j.devcel.2023.11.013 |
| PubMed: | View item in PubMed |
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