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Modelling human development and disease in pluripotent stem-cell-derived gastric organoids
Open accessAbstract
Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world's population and are largely due to chronic Helicobacter pylori infection. Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis, and there is no experimental model of normal human gastric mucosa. Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells. We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs). Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach. Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells. We used hGO cultures to identify novel signalling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3. Using hGOs to model pathogenesis of human disease, we found that H. pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signalling and induction of epithelial proliferation. Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease.
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“Thus, RA is crucial for human posterior foregut specification, consistent with the role for RA in generating foregut derivatives such as stomach endoderm in vitro (McCracken et al., 2014) and how inhibiting RA synthesis abrogates both liver and pancreas formation in zebrafish embryos (Stafford and Prince, 2002).”
From A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells (2018) · cites this paper as McCracken et al., 2014
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3D Primary Culture Model to Study Human Mammary Development
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Enteropathogenic Infections: Organoids Go Bacterial
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“pylori infection resulted in a rapid association of CagA with the c-Met receptor, activation of signaling and induction of epithelial proliferation [36].”
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BackgroundRevealing the clinical potential of high-resolution organoids
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“Secondly, the protective effect of rACE2 against the Delta variant was observed in human lung organoids, which are considered advanced, complex, and reproducible ex vivo models for studying human lung diseases.(38)”
BackgroundFrom cells to organs: progress and potential in cartilaginous organoids research
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From development to future prospects: The adipose tissue & adipose tissue organoids
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BackgroundFunctional Enterospheres Derived In Vitro from Human Pluripotent Stem Cells
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“ECAD+ cells cultured in intestinalmedium containing EGF, Noggin, and R-Spondin (ENR) gave rise to a similar number of hEnS (Figure 4A), but those that did form were larger (Figures 4B and S4) and expressed CK20 in similar numbers as MTEC spheroids (Figure 4C).”
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Metadata
- Authors
- McCracken, K. W., Catá, E. M., Crawford, C. M., Sinagoga, K. L., Schumacher, M., Rockich, B. E., Tsai, Y.-H., Mayhew, C. N., Spence, J. R., Zavros, Y., & Wells, J. M.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Cincinnati (US)
- University of Michigan (US)
- Corresponding author
- Zavros, Yana
- Wells, James M.
- ORCID
- Venue
- Nature
- Published
- 2014-10-29
- Volume
- 516
- Issue
- 7531
- Pages
- 400-404
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4270898
- OpenAlex
- W2054186703
- Cited by
- 980
- References
- 43
- Citations by year
- 2026: 54 · 2025: 67 · 2024: 87 · 2023: 69 · 2022: 104 · 2021: 106 · 2020: 96 · 2019: 79 · 2018: 82 · 2017: 93 · 2016: 86 · 2015: 50 · 2014: 6
- FWCI
- 32.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5ul1rr026314-03)
- National Institute of General Medical Sciences (T32GM063483, R01GM072915)
- National Institute of Allergy and Infectious Diseases (U19AI116491)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, K01DK091415, P30 DK0789392, R01DK083402, R01DK098350, R01DK080823, R01DK092456, P30DK078392)
- National Center for Research Resources (UL1-RR026314, U54-RR-025216)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Gastroenterology › Helicobacter pylori-related gastroenterology studies
- Keywords
- gastric organoids, human pluripotent stem cells, induced pluripotent stem cells, human embryonic stem cells, gastric epithelium, Helicobacter pylori infection, CagA, c-Met, gastric endocrine cells, Lgr5, Neurog3, signaling pathways, peptic ulcer, gastric cancer, in vitro disease model
- MeSH terms
- Cell Differentiation, Humans, Models, Biological, Organoids, Stomach, Signal Transduction, Helicobacter pylori, Helicobacter Infections, Organogenesis, Pluripotent Stem Cells
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