Optimized human intestinal organoid model reveals interleukin-22-dependency of paneth cell formation
Open accessAbstract
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.
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Time-resolved scRNA-seq on a KRAS G12D PDO treated with MRTX1133 and cetuximab showed a gradual increase in Paneth-like gene module activity over time, supporting a stepwise transition during treatment.
“We scored the CRC PDO cells for the published Paneth-like state signatures38,39 and observed a gradual increase in Paneth-like gene module activity over time (Figure S1P), supporting a stepwise transition during treatment.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [38]
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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
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Generalizing RNA velocity to transient cell states through dynamical modeling
Bergen, V., Lange, M., Peidli, S., Wolf, F. A., & Theis, F. J. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0591-3 · Cited by 2,951 · see citing works
Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Sato, T., van Es, J. H., Snippert, H. J., Stange, D. E., Vries, R. G., van den Born, M., Barker, N., Shroyer, N. F., van de Wetering, M., & Clevers, H. (2011) · Nature · doi:10.1038/nature09637 · Cited by 2,510 · see citing works
mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake
Yilmaz, Ö. H., Katajisto, P., Lamming, D. W., Gültekin, Y., Bauer-Rowe, K. E., Sengupta, S., Birsoy, K., Dursun, A., Yilmaz, V. O., Selig, M., et al. (2012) · Nature · doi:10.1038/nature11163 · Cited by 753 · see citing works
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Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
Zhang, Y., Chen, J., She, Y., Fang, Z., Zhang, Y., Ruan, D., Guo, W., Liao, J., Zhou, W., Lao, J., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.10.010 · Cited by 23 · see citing works
“We scored the CRC PDO cells for the published Paneth-like state signatures 38,39 and observed a gradual increase in Paneth-like gene module activity over time (Figure S1P), supporting a stepwise transition during treatment. scRNA-seq analysis identified seven transcriptionally distinct epithelial…”
Tan, X., Wang, X., Xu, S., Zeng, Y., Zhang, G., Xu, A., Jiang, Y., Jiang, H., Song, Y., Fan, J., et al. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s495784 · Cited by 8 · see citing works
- Authors
- He, G.-W., Lin, L., DeMartino, J., Zheng, X., Staliarova, N., Dayton, T., Begthel, H., van de Wetering, W. J., Bodewes, E., van Zon, J., Tans, S., Lopez-Iglesias, C., Peters, P. J., Wu, W., Kotlarz, D., Klein, C., Margaritis, T., Holstege, F., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Princess Máxima Center (NL)
- Institute for Atomic and Molecular Physics (NL)
- Utrecht University (NL)
- Maastricht University (NL)
- Agency for Science, Technology and Research (SG)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 29
- Issue
- 9
- Pages
- 1333-1345.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC9438971
- OpenAlex
- W4292756165
- Cited by
- 178
- References
- 7
- Citations by year
- 2026: 45 · 2025: 55 · 2024: 50 · 2023: 23 · 2022: 5
- FWCI
- 12.70
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-12-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc-nd)
- AMOLF Institutional Repository (AMOLF) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- NWO (2019.085, 737.016.009, 024.003.001)
- Ministerie van Onderwijs, Cultuur en Wetenschap
- Horizon 2020 (668294)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- IL-22, Paneth cells, intestinal stem cells, IL10RB, inflammatory bowel disease, host defense genes, REG1A, REG1B, DMBT1, tuft cells, goblet cells, enterocytes
- MeSH terms
- Interleukin-22, Calcium-Binding Proteins, DNA-Binding Proteins, Humans, Interleukins, Intestinal Mucosa, Intestine, Small, Organoids, Paneth Cells, Tumor Suppressor Proteins
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