1. Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation
- Author
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Gui-Wei He, Lin Lin, Jeff DeMartino, Xuan Zheng, Nadzeya Staliarova, Talya Dayton, Harry Begthel, Willine J. van de Wetering, Eduard Bodewes, Jeroen van Zon, Sander Tans, Carmen Lopez-Iglesias, Peter J. Peters, Wei Wu, Daniel Kotlarz, Christoph Klein, Thanasis Margaritis, Frank Holstege, Hans Clevers, Institute of Nanoscopy (IoN), RS: M4I - Nanoscopy, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
DNA-Binding Proteins ,Organoids ,Paneth Cells ,Interleukins ,Tumor Suppressor Proteins ,Calcium-Binding Proteins ,Intestine, Small ,Genetics ,Humans ,Molecular Medicine ,Cell Biology ,Intestinal Mucosa - Abstract
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.
- Published
- 2022
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