Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages

Taku Sato, Shun Ishikawa, Jumpei Asano, Hirona Yamamoto, Masayuki Fujii, Toshiro Sato, Kouhei Yamamoto, Keisuke Kitagaki, Takumi Akashi, Ryuichi Okamoto, Toshiaki Ohteki

Research output: Contribution to journalArticle

Abstract

Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation1,2, but the physiological mechanism involved in regulating that balance remains unknown. Here we describe a transcriptional regulator that preserves the stemness of ISCs by restricting their differentiation into secretory-cell lineages. Interferon regulatory factor 2 (IRF2) negatively regulates interferon signalling3, and mice completely lacking Irf24 or with a selective Irf2 deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5hi ISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state in Irf2-deficient mice, regeneration of their intestinal epithelia after 5-fluorouracil-induced damage was severely impaired. Similarly, extended treatment with low-dose poly(I:C) or chronic infection of lymphocytic choriomeningitis virus clone 13 (LCMV C13)5 caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base of Irf2−/− as well as LCMV C13-infected wild-type mice, indicating that excess interferon signalling directs ISCs towards a secretory-cell fate. Collectively, our findings indicate that regulated interferon signalling preserves ISC stemness by restricting secretory-cell differentiation.

Original languageEnglish
Pages (from-to)919-926
Number of pages8
JournalNature Cell Biology
Volume22
Issue number8
DOIs
Publication statusPublished - 2020 Aug 1

ASJC Scopus subject areas

  • Cell Biology

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    Sato, T., Ishikawa, S., Asano, J., Yamamoto, H., Fujii, M., Sato, T., Yamamoto, K., Kitagaki, K., Akashi, T., Okamoto, R., & Ohteki, T. (2020). Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages. Nature Cell Biology, 22(8), 919-926. https://doi.org/10.1038/s41556-020-0545-5