Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation
He, Gui Wei; Lin, Lin; DeMartino, Jeff; Zheng, Xuan; Staliarova, Nadzeya; Dayton, Talya; Begthel, Harry; van de Wetering, Willine J.; Bodewes, Eduard; van Zon, Jeroen; Tans, Sander; Lopez-Iglesias, Carmen; Peters, Peter J.; Wu, Wei; Kotlarz, Daniel; Klein, Christoph; Margaritis, Thanasis; Holstege, Frank; Clevers, Hans
(2022) Cell stem cell, volume 29, issue 9, pp. 1333 - 1345.e6
(Article)
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,
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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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Keywords: anti-microbial proteins, enterocytes, IL-22, IL10RB, inflammatory bowel disease, intestinal stem cells, mTOR, organoids, Paneth cells, regeneration, Molecular Medicine, Genetics, Cell Biology
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We thank Stieneke van den Brink for RSPO1-conditioned medium production, Jeroen Korving for histological staining support, Reinier van der Linden for FACS support, Dr. Kai Kretzschmar for generating the original wild-type human intestinal organoid line, and Drs. Joep Beumer and Delilah Hendriks for providing the MUC2 reporter line. Illustrative diagrams were created with BioRender.com. This publication is part of the project Organoid in time with project number 2019.085 of the research program NWO Investment Large, which is financed by the Dutch Research Council (NWO) and the NWO building blocks of life project, cell dynamics within lung and intestinal organoids (737.016.009), by the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. Supported by the European Union's Horizon 2020 research and innovation program INTENS (668294). G.-W.H. L.L. and H.C. conceptualized the project, interpreted the results, and wrote the manuscript. G.-W.H. and L.L. designed and performed major experiments and analyzed data. J.D. T.M. F.H. and E.B. performed the scRNA-seq experiments and analysis. N.S. and W.W. performed the proteomic experiments and analysis. X.Z. J.v.Z. and S.T. performed imaging-based tracking experiments and analysis. C.L.-I. W.J.v.d.W. and P.J.P. performed transmission electron microscopy. H.B. performed immunohistochemistry staining. T.D. isolated and provided human intestinal organoid lines from additional donors. D.K. and C.K. provided human samples. H.C. is an inventor of several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. Funding Information: This publication is part of the project Organoid in time with project number 2019.085 of the research program NWO Investment Large, which is financed by the Dutch Research Council ( NWO ) and the NWO building blocks of life project, cell dynamics within lung and intestinal organoids (737.016.009), by the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project ( 024.003.001 ) funded by the Ministry of Education, Culture and Science of the government of the Netherlands . Supported by the European Union’s Horizon 2020 research and innovation program INTENS ( 668294 ). Publisher Copyright: © 2022 The Authors
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