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IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3

Authors: Zhu, Pingping; Zhu, Xiaoxiao; Wu, Jiayi; He, Luyun Lei; Lu, Tiankun; Wang, Yanying; Liu, Benyu; Ye, Buqing; Sun, Lei; Fan, Dongdong; Wang, Jing; Yang, Liuliu; Qin, Xiwen; Du, Ying; Li, Chong; He, Luyun Lei; Ren, Weizheng; Wu, Xin; Tian, Yong; Fan, Zusen

Online: http://dx.doi.org/10.1038/s41590-018-0297-6

Issue: Nat Immunol. 2019 Feb;20(2):183-194.


Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5+ ISCs showed high expression of the immune cell-associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5+ ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 (Il13ra1) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13‒IL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with β-catenin in rendering its nuclear translocation, which caused activation of the β-catenin pathway and the maintenance of Lgr5+ ISCs.