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Redundant Sources of Wnt Regulate Intestinal Stem Cells and Promote Formation of Paneth Cells
Open accessAbstract
Background & aims Wnt signaling regulates multiple aspects of intestinal physiology, including stem cell maintenance. Paneth cells support stem cells by secreting Wnt, but little is known about the exact sources and primary functions of individual Wnt family members.Methods We analyzed intestinal tissues and cultured epithelial cells from adult mice with conditional deletion of Wnt3 (Vil-CreERT2;Wnt3fl/fl mice). We also analyzed intestinal tissues and cells from Atoh1 mutant mice, which lack secretory cells.Results Unexpectedly, Wnt3 was dispensable for maintenance of intestinal stem cells in mice, indicating a redundancy of Wnt signals. By contrast, cultured crypt organoids required Paneth cell-derived Wnt3. Addition of exogenous Wnt, or coculture with mesenchymal cells, restored growth of Vil-CreERT2;Wnt3fl/fl crypt organoids. Intestinal organoids from Atoh1 mutant mice did not grow or form Paneth cells; addition of Wnt3 allowed growth in the absence of Paneth cells. Wnt signaling had a synergistic effect with the Lgr4/5 ligand R-spondin to induce formation of Paneth cells. Mosaic expression of Wnt3 in organoids using a retroviral vector promoted differentiation of Paneth cells in a cell-autonomous manner.Conclusions Wnt is part of a signaling loop that affects homeostasis of intestinal stem and Paneth cells in mice. Wnt3 signaling is required for growth and development of organoid cultures, whereas nonepithelial Wnt signals could provide a secondary physiological source of Wnt.
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“Quantitative real-time RT-PCR analyses for expression of Wnt1, 2, 2b, 3, 3a, 8a, 8b, 10a, and 10b (Farin et al., 2012) in ISCs demonstrated reduced Wnt3 (Figure 3C) levels in aged ISCs.”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2012
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Li, L. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727174751.793554910
Alison, M. R. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737406582.793571991
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Cellular Heterogeneity during Metastatic Colonization of Colorectal Cancer
Heinz, M. C. (2022) · Utrecht University Repository (Utrecht University) · doi:10.33540/1556
Ai, L.-S., & Yu, Y. (2022) · World Chinese Journal of Digestology · doi:10.11569/wcjd.v30.i23.1009
Mosa, M. H., Michels, B. E., Menche, C., Nicolas, A. M., Darvishi, T., Greten, F. R., & Farin, H. F. (2023) · doi:10.1158/0008-5472.c.6512463
Self-citationMosa, M. H., Michels, B. E., Menche, C., Nicolas, A. M., Darvishi, T., Greten, F. R., & Farin, H. F. (2023) · doi:10.1158/0008-5472.c.6512463.v1
Self-citationMartín, M. L., Adileh, M., Hsu, K., Hua, G., Lee, S. G., Li, C., Fuller, J. D., Rotolo, J. A., Bodo, S., Klingler, S., et al. (2023) · doi:10.1158/0008-5472.c.6511909
Kim, Y., Kang, M. H., Kim, G., & Cho, Y. (2023) · Organoid · doi:10.51335/organoid.2023.3.e4
Human intestinal organoid-derived PDGFRα+ mesenchymal stroma empowers LGR4+ epithelial stem cellsPreprint
JunLong, C., Horiuchi, S., Kuramochi, S., Kawasaki, T., Kawasumi, H., Akiyama, S., Arai, T., Morinaga, K., Kimura, T., Kiyono, T., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.16.553630
Metadata
- Authors
- Farin, H. F., Van Es, J. H., & Clevers, H.
- Affiliations
- University Medical Center Utrecht (NL)
- Corresponding author
- Clevers, Hans
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 143
- Issue
- 6
- Pages
- 1518-1529.e7
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2038714514
- Cited by
- 655
- References
- 55
- Citations by year
- 2026: 25 · 2025: 38 · 2024: 39 · 2023: 54 · 2022: 48 · 2021: 68 · 2020: 56 · 2019: 55 · 2018: 57 · 2017: 57 · 2016: 34 · 2015: 41 · 2014: 37 · 2013: 41 · 2012: 4
- FWCI
- 15.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Funders
- European Molecular Biology Organization
- Top Institute Pharma
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Gastroenterology › Digestive system and related health
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- Wnt signaling, Wnt3, intestinal stem cells, Paneth cells, R-spondin, Atoh1, mesenchymal cells, intestinal homeostasis
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Epithelial Cells, Homeostasis, Intestine, Small, Mice, Transgenic, Stem Cells, Signal Transduction, Paneth Cells, Models, Animal, Mice, Wnt3 Protein, In Vitro Techniques
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