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
  • 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: [email protected].
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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