IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon

Kana Minamide,Toshiaki Ohteki,Tamotsu Kato,Taku Sato,Yusuke Nakanishi,Hiroshi Ohno,Jumpei Asano

doi:10.1038/s41598-020-71633-3

Abstract

The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown. We previously reported that type I interferon (IFN), which is essential for host antiviral responses, is a physiological stressor for hematopoietic stem cells (HSCs) and small intestinal stem cells (ISCs) and that interferon regulatory factor-2 (IRF2), which attenuates IFN signaling, maintains their stemness. Here, using a dextran sodium sulfate (DSS)-induced colitis model, we explore the role of IRF2 in maintaining colonic epithelial stem cells (CoSCs). In mice with a conditional Irf2 deletion in the intestinal epithelium (hereafter Irf2ΔIEC mice), both the number and the organoid-forming potential of CoSCs were markedly reduced. Consistent with this finding, the ability of Irf2ΔIEC mice to regenerate colon epithelium after inducing colitis was severely impaired, independently of microbial dysbiosis. Mechanistically, CoSCs differentiated prematurely into transit-amplifying (TA) cells in Irf2ΔIEC mice, which might explain their low CoSC counts. A similar phenotype was induced in wild-type mice by repeated injections of low doses of poly(I:C), which induces type I IFN. Collectively, we demonstrated that chronic IFN signaling physiologically stresses CoSCs. This study provides new insight into the development of colitis and molecular mechanisms that maintain functional CoSCs throughout life.

Highlights

The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown
We found that deleting Irf[2] in the intestinal epithelium of mice reduced the number of colonic epithelial stem cells (CoSCs) and severely impaired epithelial regeneration after the development of dextran sodium sulfate (DSS)-induced colitis
Irf2ΔIEC mice had no obvious abnormalities in the colonic epithelial layer, including the crypt shape and the size, the development and distribution of goblet cells, and the number of Ki67+ proliferating cells, indicating that interferon regulatory factor-2 (IRF2) is dispensable for the development and physiologic turnover of the colonic epithelium (Fig. 1A)

Summary

Introduction

The physiological stresses that diminish tissue stem-cell characteristics remain largely unknown. In mice with a conditional Irf[2] deletion in the intestinal epithelium (hereafter Irf2ΔIEC mice), both the number and the organoid-forming potential of CoSCs were markedly reduced Consistent with this finding, the ability of Irf2ΔIEC mice to regenerate colon epithelium after inducing colitis was severely impaired, independently of microbial dysbiosis. We found that deleting Irf[2] in the intestinal epithelium of mice reduced the number of CoSCs and severely impaired epithelial regeneration after the development of DSS-induced colitis. We confirmed that the organoid-forming potential of CoSCs in wild-type (WT) mice was substantially reduced by ongoing treatment with low doses of poly(I:C), which induces type I IFN in vivo, indicating that chronic IFN signaling causes CoSC function to decline. IRF2 plays a critical role in preserving the stemness of CoSCs by suppressing physiological IFN signaling

Methods

Results

Conclusion