2. Academic Validation
  3. Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation

Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation

  • Cell Stem Cell. 2022 Sep 1;29(9):1333-1345.e6. doi: 10.1016/j.stem.2022.08.002.
Gui-Wei He 1,  Lin Lin 2,  Jeff DeMartino 3,  Xuan Zheng 4,  Nadzeya Staliarova 5,  Talya Dayton 1,  Harry Begthel 1,  Willine J van de Wetering 6,  Eduard Bodewes 3,  Jeroen van Zon 4,  Sander Tans 4,  Carmen Lopez-Iglesias 6,  Peter J Peters 6,  Wei Wu 7,  Daniel Kotlarz 8,  Christoph Klein 8,  Thanasis Margaritis 3,  Frank Holstege 3,  Hans Clevers 9
Affiliations

Affiliations

  • 1 Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, Utrecht, 3584 CT, the Netherlands.
  • 2 Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, Utrecht, 3584 CT, the Netherlands; The Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands.
  • 3 The Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands.
  • 4 AMOLF, Amsterdam, the Netherlands.
  • 5 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands.
  • 6 The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, 6229 ER Maastricht, the Netherlands.
  • 7 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands; Singapore Immunology Network (SIgN), ASTAR (Agency for Science, Technology and Research), Singapore.
  • 8 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
  • 9 Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Uppsalalaan 8, Utrecht, 3584 CT, the Netherlands; The Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu.
PMID: 36002022 DOI: 10.1016/j.stem.2022.08.002
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.

Keywords

IL-22; IL10RB; Paneth cells; anti-microbial proteins; enterocytes; inflammatory bowel disease; intestinal stem cells; mTOR; organoids; regeneration.

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