The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells
While the intestinal epithelium has the highest cellular turnover rates in the mammalian body, it is also considered one of the tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards intestinal stem cells (ISCs) from environmental conditions in the aged intestine. Using in vivo phenotypic analysis, transcriptomics, and in vitro intestinal organoid studies, we show that age-dependent activation of interferon-γ (IFN-γ) signaling and inactivation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling are responsible for establishing an equilibrium of Lgr5<sup>+</sup> ISCs-between active and quiescent states-to preserve the ISC pool during aging. Furthermore, we show that differentiated cells have different sensitivities to each of the two signaling pathways, which may induce aging-related, functional, and metabolic changes in the body. Thus, our findings reveal an exquisitely balanced, age-dependent signaling mechanism that preserves stem cells at the expense of differentiated cells.
Authors
- Mitinori Saitou (ORCID: https://orcid.org/0000-0002-2895-6798)
- Takuya Yamamoto (ORCID: https://orcid.org/0000-0002-0022-3947)
- May Nakajima‐Koyama
- Satoko Sakurai (ORCID: https://orcid.org/0009-0008-6781-2122)
- Tomonori Nakamura (ORCID: https://orcid.org/0000-0002-0173-0780)
- Eisuke Nishida (ORCID: https://orcid.org/0000-0002-9225-0263)
- Yasuaki Hiraoka (ORCID: https://orcid.org/0000-0002-1023-2687)
- Mio Kabata
- Kohei Kometani (ORCID: https://orcid.org/0000-0003-4281-4371)
- Mizuki Kimura
- Akira Hirota (ORCID: https://orcid.org/0000-0003-3301-089X)
- Yusuke Imoto (ORCID: https://orcid.org/0000-0003-2574-4471)
- Yuko Sogabe (ORCID: https://orcid.org/0000-0002-0623-3871)
- Joon-Seong Lee
- Yoko Hamazaki (ORCID: https://orcid.org/0000-0002-3911-5708)
Institutions
- Kyoto University (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- RIKEN Center for Advanced Intelligence Project (JP)
- Kyoto University Hospital (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1016/j.celrep.2025.115286
- Citations
- 7
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology