Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating all differentiated cell types while maintaining an active stem cell compartment. IL-22 does not promote the expansion of stem cells but rather slows the growth of hSIOs. In hSIOs, IL-22 is required for formation of Paneth cells, the prime producers of intestinal antimicrobial peptides (AMPs). Introduction of inflammatory bowel disease (IBD)-associated loss-of-function mutations in the IL-22 co-receptor gene IL10RB resulted in abolishment of Paneth cells in hSIOs. Moreover, IL-22 induced expression of host defense genes (such as REG1A, REG1B, and DMBT1) in enterocytes, goblet cells, Paneth cells, Tuft cells, and even stem cells. Thus, IL-22 does not directly control the regenerative capacity of crypt stem cells but rather boosts Paneth cell numbers, as well as the expression of AMPs in all cell types.

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Elsevier/ Cell Press
The Netherlands Organisation for Scientific Research (NWO) , European Union Horizon 2020
Cell Stem Cell
Quantitative Developmental Biology

He, G.-W., Lin, L., DeMartino, J., Zheng, X., Staliarova, N., Dayton, T., … Clevers, H. (2022). Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation. Cell Stem Cell, 29(9), 1333–1345.e6. doi:10.1016/j.stem.2022.08.002