Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages
Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages
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受调节的干扰素信号传导通过限制分化为分泌细胞谱系来保持肠道干细胞的干性
DOI：
10.1038/s41556-020-0545-5
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发表时间：
2020
期刊：
影响因子：
21.3
通讯作者：
Ohteki T.
中科院分区：
文献类型：
--
作者：
Sato T;Ishikawa S;Asano J;Yamamoto H;Fujii M;Sato T;Yamamoto K;Kitagaki K;Akashi T;Okamoto R;Ohteki T.
肠干细胞（ISCs）位于隐窝基底，并微调其自我更新和分化的平衡，但参与调节该平衡的生理机制仍不清楚。在这里，我们描述了一种转录调节因子，通过限制ISCs分化为分泌细胞谱系来保持ISCs的干细胞性。干扰素调节因子2（IRF 2）负调节干扰素信号，在肠上皮细胞中完全缺乏IRF 2或选择性IRF 2缺失的小鼠具有比对照小鼠显著更少的隐窝Lgr 5 hiISCs。尽管Irf 2缺陷小鼠在稳态时肠上皮细胞的完整性未受损，但在5-氟尿嘧啶诱导的损伤后肠上皮细胞的再生严重受损。类似地，低剂量poly（I：C）的延长治疗或淋巴细胞性脉络丛脑膜炎病毒克隆13（LCMV C13）的慢性感染引起野生型小鼠中ISCs的功能下降。相反，在Irf 2 −/−以及LCMV C13感染的野生型小鼠的隐窝基底发现大量未成熟的潘氏细胞聚集，表明过量的干扰素信号传导将ISC导向分泌细胞的命运。总的来说，我们的研究结果表明，调节干扰素信号通过限制分泌细胞分化来保持ISC干性。
Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation,, 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 signalling, and mice completely lackingIrf2or with a selectiveIrf2deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5hiISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state inIrf2-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) caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base ofIrf2−/−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.
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影响因子：
20.3
作者：
Kamphuis, Elisabeth;Junt, Tobias;Kalinke, Ulrich
通讯作者：
Kalinke, Ulrich
影响因子：
30.3
作者：
Sun L;Miyoshi H;Origanti S;Nice TJ;Barger AC;Manieri NA;Fogel LA;French AR;Piwnica-Worms D;Piwnica-Worms H;Virgin HW;Lenschow DJ;Stappenbeck TS
通讯作者：
Stappenbeck TS
5-氟尿嘧啶引起的炎症性肠道损伤需要 IL-4。
影响因子：
3.8
作者：
P. Soares;J. M. Mota;E. Souza;P. Justino;Á. X. Franco;F. Cunha;R. Ribeiro;M. H. Souza
通讯作者：
M. H. Souza
影响因子：
2.7
作者：
Andreu, Pauline;Peignon, Gregory;Romagnolo, Beatrice
通讯作者：
Romagnolo, Beatrice