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

Nature Cell Biology
Taku SatoToshiaki Ohteki

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....Continue Reading

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Citations

Jan 6, 2021·International Journal of Molecular Sciences·Ken KurokawaKazuhiko Koike
Mar 28, 2021·Nature Reviews. Immunology·Andrés R Muñoz-Rojas, Diane Mathis
Jun 17, 2021·International Immunology·Toshiaki OhtekiNobuyuki Onai

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Datasets Mentioned

BETA
GSE51398
GSE66751

Methods Mentioned

BETA
IECs
IEC
fluorescence-activated cell sorting
immunoprecipitation
transgenic
PCR
FCS
FACS
chip

Software Mentioned

R package gplots
GSEA
MEME
Image J
H3C
R
HOMER
DAVID
Gene Set Enrichment Analysis ( GSEA )
BZ

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