02501nas a2200589   4500000000100000000000100001008004100002260001500043653002900058653002500087653001100112653001000123653001100133653001700144653002200161653002100183653001400204653001700218653001700235653003000252653002800282653001600310653003100326653002600357653000900383653001400392653001700406100001500423700001200438700001900450700001500469700002300484700001700507700001800524700003100542700001900573700001900592700001600611700002600627700002000653700001100673700001900684700002000703700002400723700001900747700001700766245010500783300001700888490000700905520098500912022001401897       2022                            d  c2022-09-0110aCalcium-Binding Proteins10aDNA-Binding Proteins10aHumans10aIL-2210aIL10RB10aInterleukins10aIntestinal Mucosa10aIntestine, Small10aorganoids10aPaneth Cells10aPaneth Cells10aTumor Suppressor Proteins10aanti-microbial proteins10aenterocytes10ainflammatory bowel disease10aintestinal stem cells10amTOR10aorganoids10aRegeneration1 aGui-Wei He1 aLin Lin1 aJeff DeMartino1 aXuan Zheng1 aNadzeya Staliarova1 aTalya Dayton1 aHarry Begthel1 aWilline J. van de Wetering1 aEduard Bodewes1 aJeroen van Zon1 aSander Tans1 aCarmen Lopez-Iglesias1 aPeter J. Peters1 aWei Wu1 aDaniel Kotlarz1 aChristoph Klein1 aThanasis Margaritis1 aFrank Holstege1 aHans Clevers00aOptimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation  a1333-1345.e60 v293 aOpposing 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.  a1875-9777