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

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-13R alpha 1 (Il13r alpha 1) in ISCs to increase its stability, which led to the expression of IL-13R alpha 1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13R alpha 1 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 beta-catenin in rendering its nuclear translocation, which caused activation of the beta-catenin pathway and the maintenance of Lgr5(+) ISCs.