The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells

• DOI: 10.1016/j.celrep.2025.115286
• Publication Date: 2025-02-13T22:01:29Z
• Authors: May Nakajima-Koyama; Mio Kabata; Joonseong Lee; Yuko Sogabe; Satoko Sakurai; Akira Hirota; Mizuki Kimura; Tomonori Nakamura; Yusuke Imoto; Kohei Kometani; Yoko Hamazaki; Yasuaki Hiraoka; Mitinori Saitou; Eisuke Nishida; Takuya Yamamoto

Highlights•IFN-γ and ERK/MAPK signaling activities alter upon aging in the small intestine•The balanced between IFN-γ maintain ISC pool•An equilibrium active quiescent states exists aged ISCs•Changes two pathways affect functions of differentiated cellsSummaryWhile intestinal epithelium has highest cellular turnover rates mammalian body, it is also considered one tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards stem cells (ISCs) from environmental conditions intestine. Using vivo phenotypic analysis, transcriptomics, vitro organoid studies, show age-dependent activation interferon-γ (IFN-γ) inactivation extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) are responsible for establishing Lgr5+ ISCs—between states—to preserve pool during aging. Furthermore, have different sensitivities each pathways, which may induce aging-related, functional, metabolic changes body. Thus, our findings exquisitely balanced, preserves at expense cells.Graphical abstract