Cited by 656Wnt/β-catenin signaling in development and cancerDigestive system and related healthCancer Cells and Metastasis

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Redundant Sources of Wnt Regulate Intestinal Stem Cells and Promote Formation of Paneth Cells

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Farin, Henner F., Van Es, Johan H., Clevers, Hans·2012·Gastroenterology

DOI 10.1053/j.gastro.2012.08.031

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Abstract

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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Authors: Farin, H. F., Van Es, J. H., & Clevers, H.
Affiliations: University Medical Center Utrecht (NL)
Corresponding author: Clevers, Hans
ORCID: Farin, Henner F.
Clevers, Hans
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2012-12
Volume: 143
Issue: 6
Pages: 1518-1529.e7
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2012.08.031
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Redundant Sources of Wnt Regulate Intestinal Stem Cells and Promote Formation of Paneth Cells

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