Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche
Open accessAbstract
The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.
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Organoids represent robust in vitro cultures that preserve tissue architecture, stem cell activity, multilineage differentiation, genomic alterations, histology, and pathology of primary tissues.
“Organoids represent robust in vitro cultures that preserve tissue architecture, stem cell activity, multilineage differentiation, genomic alterations, histology, and pathology of primary tissues1,2.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [2]
The Results section, “Establishment of a long-term intestinal culture system” (page not provided), describes long-lived mouse intestinal organoids with polarized tissue structure, proliferative zones, and multilineage differentiation; the paper also reports putative intestinal stem-cell populations. It does not show that the cultures preserve genomic alterations or the pathology of primary tissues, and its findings are specific to intestinal cultures rather than organoids generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe Ootani method uses collagen I gel in which small and large intestinal cells are kept suspended at an air-liquid interface; this method improves oxygenation of the organoid, allows viable murine organoids to be maintained in culture for up to 350 days, and preserves the mesenchymal niche in the organoids.
“In contrast to the TMDU method, the Ootani method uses collagen I gel in which small and large intestinal cells are kept suspended at an air-liquid interface; this method improves oxygenation of the organoid, allows viable murine organoids to be maintained in culture for up to 350 days, and preserves the mesenchymal niche in the organoids90.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [90]
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- Authors
- Ootani, A., Li, X., Sangiorgi, E., Ho, Q. T., Ueno, H., Toda, S., Sugihara, H., Fujimoto, K., Weissman, I. L., Capecchi, M. R., & Kuo, C. J.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Saga University (JP)
- Corresponding author
- Ootani, Akifumi
- Kuo, Calvin J
- Venue
- Nature Medicine
- Published
- 2009-04-27
- Volume
- 15
- Issue
- 6
- Pages
- 701-706
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2919216
- OpenAlex
- W2062004524
- Cited by
- 906
- References
- 41
- Citations by year
- 2026: 40 · 2025: 60 · 2024: 44 · 2023: 57 · 2022: 68 · 2021: 81 · 2020: 85 · 2019: 59 · 2018: 67 · 2017: 72 · 2016: 46 · 2015: 40 · 2014: 47 · 2013: 44 · 2012: 47
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA086065, R01 CA86065-06)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085720, U01DK085527, R01DK069989, P30DK056339, P30DK56339)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- intestinal organoids, intestinal stem cells, Wnt signaling, Notch signaling, air-liquid interface culture, RSPO1, DKK1, gamma-secretase inhibitors, neurogenin 3, goblet cell differentiation, Lgr5, BMI1, multilineage differentiation, intestinal epithelium, stem cell niche
- MeSH terms
- Aging, Animals, Epithelial Cells, Immunoglobulins, Intestinal Mucosa, Intestines, Microscopy, Electron, Nerve Tissue Proteins, Time Factors, Signal Transduction, Thrombospondins, Tissue Culture Techniques, Wnt Proteins, Mice, Basic Helix-Loop-Helix Proteins, Receptors, Notch, Stem Cell Niche
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