Interleukin-22 directly regulates intestinal stem cell regeneration after tissue damage (MUC8P.722)

Abstract

Abstract Little is known about regulation of the intestinal stem cell (ISC) compartment after injury. We hypothesized that IL-22 could promote intestinal regeneration by either acting on ISCs or by acting on Paneth cells (PCs) making up the ISC niche. Utilizing an in vitro regeneration model, we found that organoids derived from murine small intestine (SI) and large intestine (LI) crypts demonstrated substantially increased size after culture with IL-22. Innate lymphoid cell co-culture also increased organoid size in an IL-22-dependent fashion. IL-22 expanded the Lgr5+ ISC pool within SI organoids, activated STAT3 phosphorylation in Lgr5+ cells, and increased size of organoids cultured from purified SI ISCs. Using a murine allogeneic bone marrow transplant (BMT) model, we found that IL-22 administration led to reduced intestinal graft vs. host disease pathology, increased maintenance of Lgr5+ ISCs, and significantly greater ISC proliferation. ISC protection post-BMT was not due to niche augmentation, as PC numbers, PC-derived growth factors (EGF, Wnt3), and stroma-derived growth factors (R-spondin3) were all unchanged after IL-22 administration. IL-22 receptor (IL-22R) staining further indicated a direct effect of IL-22 on ISCs rather than the niche, as PCs were found to express very little IL-22R and demonstrated no evidence of STAT3 phosphorylation upon in vitro culture. In summary, we found that IL-22 regulates epithelial regeneration after tissue damage by acting directly on ISCs.