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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RA is crucial for human posterior foregut specification.
“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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Identification of proliferative and mature β-cells in the islets of Langerhans
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Human disease models in drug development
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Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary
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“Inhibition of BMP signaling, in conjunction with FGF and Wnt activation, is required to repress Cdx2 and the posterior program and instead promotes the formation of Sox2-expressing foregut endoderm (McCracken et al., 2014).”
BackgroundInfluentialSelf-citationMulti-lineage human iPSC-derived platforms for disease modeling and drug discovery
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“, 2017), and stomach (Broda et al., 2019; McCracken et al., 2017; McCracken et al., 2014) have been replicated using hiPSC-derived organoids.”
BackgroundModeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond
Liu, C., Oikonomopoulos, A., Sayed, N., & Wu, J. C. (2018) · Development · doi:10.1242/dev.156166 · Cited by 271 · see citing works
“…injury (Musah et al., 2017) Pancreas Organoid Pancreatic facets of cystic fibrosis (Hohwieler et al., 2017) Stomach Organoid H. pylori infection (McCracken et al., 2014) Heart Engineered tissue Dilated cardiomyopathy (Hinson et al., 2015; Tiburcy et al., 2017), heart failure (Tiburcy et al.,…”
BackgroundOrganoids: The current status and biomedical applications
Yang, S., Hu, H., Kung, H., Zou, R.-Q., Dai, Y.-S., Hu, Y.-F., Wang, T., Lv, T., Yu, J., & Li, F. (2023) · MedComm · doi:10.1002/mco2.274 · Cited by 282 · see citing works
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Modeling neoplastic disease with spheroids and organoids
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“3) including colon [121–125], breast [118, 126], liver [127, 128], lung [129, 130], pancreas [131, 132], endometrium [133], stomach [119, 134, 135], prostate [136, 137], ovary [138], bladder [139, 140], kidney [141–143], brain [144, 145], bone [146, 147], and esophagus [148, 149].”
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“In Vitro and In Vivo To determine if in vitro-derived HIOs and HCOs express markers of stem and progenitor cells, we used the H9-BAC-LGR5-eGFP transgenic line that has been described previously (McCracken et al., 2014; Watson et al., 2014).”
BackgroundMethodInfluentialSelf-citationEvaluation of variability in human kidney organoids
Phipson, B., Er, P. X., Combes, A. N., Forbes, T. A., Howden, S. E., Zappia, L., Yen, H.-J., Lawlor, K. T., Hale, L. J., Sun, J. Q. J., et al. (2018) · Nature Methods · doi:10.1038/s41592-018-0253-2 · Cited by 256 · see citing works
Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells
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Organoid Models of Human Gastrointestinal Development and Disease
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Self-citationOrgans-on-a-chip models for biological research
Vunjak-Novakovic, G., Ronaldson-Bouchard, K., & Radisic, M. (2021) · Cell · doi:10.1016/j.cell.2021.08.005 · Cited by 248 · see citing works
“The inclusionof apatient’smicrobiome into multi-organ models allows predictive insights into how a patient will respond to a drug therapy (McCracken et al., 2014).”
BackgroundSigal, M. J., Rothenberg, M. E., Logan, C. Y., Lee, J. Y., Honaker, R. W., Cooper, R. L., Passarelli, B., Camorlinga, M., Bouley, D. M., Cabrera-Álvarez, G., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.02.049 · Cited by 244 · see citing works
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Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models
Urzì, O., Gasparro, R., Costanzo, E., Luca, A. D., Giavaresi, G., Fontana, S., & Alessandro, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512046 · Cited by 247 · see citing works
“Several organoids have been established in vitro to date, including pancreas organoids [21,22], thyroid organoids [23], gastric organoids [24], liver organoids [25], brain organoids [26], lung organoids [27], and retina organoids [28].”
BackgroundHigh-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells
Beumer, J., Puschhof, J., Bauzá‐Martinez, J., Martínez-Silgado, A., Elmentaite, R., James, K. R., Ross, A., Hendriks, D. F. G., Artegiani, B., Busslinger, G. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.036 · Cited by 224 · see citing works
Nonadhesive Alginate Hydrogels Support Growth of Pluripotent Stem Cell-Derived Intestinal Organoids
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Self-citationOrganoids and organs-on-chips: Insights into human gut-microbe interactions
Puschhof, J., Pleguezuelos‐Manzano, C., & Clevers, H. C. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.04.002 · Cited by 226 · see citing works
A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells
Ang, L. T., Tan, A. K. Y., Autio, M. I., Goh, S. H., Choo, S. H., Lee, K. L., Tan, J., Pan, B., Lee, J. J. H., Lum, J. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.087 · Cited by 220 · see citing works
“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).”
BackgroundWnt/β-catenin promotes gastric fundus specification in mice and humans
McCracken, K. W., Aihara, E., Martin, B., Crawford, C. M., Broda, T. R., Tréguier, J., Zhang, X., Shannon, J. M., Montrose, M. H., & Wells, J. M. (2017) · Nature · doi:10.1038/nature21021 · Cited by 222 · see citing works
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Bioengineering Approaches for the Advanced Organoid Research
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Stem cell-derived organoids and their application for medical research and patient treatment
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“Human gastric organoids can be infected with the gastric pathogen Helicobacter pylori and the model recapitulates the known hallmarks of infection [13, 34].”
InfluentialBacterial infections and cancer
van Elsland, D. M., & Neefjes, J. (2018) · EMBO Reports · doi:10.15252/embr.201846632 · Cited by 216 · see citing works
“Another H. pylori virulence factor, cytotoxin-associated gene A (CagA), which depends on the type IV pilus cell-surface adhesion CagL for its host cell targeting, interacts with the c-Met receptor to activate epithelial proliferation, as shown in human gastric organoids [67].”
Gao, S., Yan, L., Wang, R., Li, J., Yong, J., Zhou, X., Wei, Y., Wu, X., Wang, X., Fan, X., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0105-4 · Cited by 213 · see citing works
Kim, W., Gwon, Y., Park, S., Kim, H., & Kim, J. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.03.039 · Cited by 211 · see citing works
AI-enabled organoids: Construction, analysis, and application
Bai, L., Wu, Y., Li, G., Zhang, W., Zhang, H., & Su, J. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.09.005 · Cited by 216 · see citing works
Mini-Gut Organoids: Reconstitution of the Stem Cell Niche
Date, S., & Sato, T. (2015) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100814-125218 · Cited by 205 · see citing works
“Organoids also recapitulate different absorptive and digestive functions determined by the proximal-distal intestinal axis (Middendorp et al. 2014).”
Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells
Kurmann, A. A., Serra, M., Hawkins, F., Rankin, S. A., Mori, M., Astapova, I., Ullas, S., Lin, S., Bilodeau, M., Rossant, J., et al. (2015) · Cell Stem Cell · doi:10.1016/j.stem.2015.09.004 · Cited by 204 · see citing works
“Recent progress in the differentiation of pluripotent stem cells (PSCs) in vitro has allowed the derivation of desired cell lineages and in some instances their in vitro self-assembly into 3D structures, referred to as organoids (Lancaster and Knoblich, 2014; McCracken et al., 2014).”
Organoids: a systematic review of ethical issues
de Jongh, D., Massey, E. K., Berishvili, E., Fonseca, L. M., Lebreton, F., Bellofatto, K., Bignard, J., Seißler, J., Buerck, L. W.-V., Honarpisheh, M. M., et al. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02950-9 · Cited by 208 · see citing works
“Human organoids have been successfully generated for a wide range of organs, including the gut [6, 7], lung [8], thyroid [9], gastric [10], heart [11], kidney [12, 13], liver [14], brain [15–19], and retina [20].”
BackgroundOrganoids for Drug Discovery and Personalized Medicine
Takahashi, T. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021108 · Cited by 202 · see citing works
Organoid models of gastrointestinal cancers in basic and translational research
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Collateral damage: Insights into bacterial mechanisms that predispose host cells to cancer
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Use and application of 3D-organoid technology
Artegiani, B., & Clevers, H. C. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy187 · Cited by 190 · see citing works
A human liver organoid screening platform for DILI risk prediction
Zhang, C. J., Meyer, S. R., O’Meara, M. J., Huang, S., Capeling, M. M., Ferrer-Torres, D., Childs, C. J., Spence, J. R., Fontana, R. J., & Sexton, J. Z. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.01.019 · Cited by 199 · see citing works
Self-citationApplications of organoids for cancer biology and precision medicine
Lo, Y.-H., Karlsson, K., & Kuo, C. J. (2020) · Nature Cancer · doi:10.1038/s43018-020-0102-y · Cited by 182 · see citing works
Xu, H., Jiao, Y., Qin, S., Zhao, W., Chu, Q., & Wu, K. (2018) · Experimental Hematology and Oncology · doi:10.1186/s40164-018-0122-9 · Cited by 184 · see citing works
Organoid culture systems to study host–pathogen interactions
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“Colonization of the bacteria led to an increase in proliferation of Lgr5 + stem cells which was in turn found to be induced by bacterial virulence factor CagA expression [44 ] .”
BackgroundIn Vitro Models to Study Human Lung Development, Disease and Homeostasis.
Miller, A. J., & Spence, J. (2017) · Physiology · doi:10.1152/physiol.00041.2016 · Cited by 166 · see citing works
Self-citationHill, D. R., Huang, S., Nagy, M. S., Yadagiri, V. K., Fields, C., Thornhill, D., Bons, B., Dedhia, P. H., Chin, A. M., Tsai, Y.-H., et al. (2017) · eLife · doi:10.7554/elife.29132 · Cited by 173 · see citing works
“…al., 2014; Dedhia et al., 2016; Aurora and Spence, 2016; Chin et al., 2017) and recent work has established gastrointestinal organoids as a powerful model of microbial pathogenesis at the mucosal interface (Leslie et al., 2015; McCracken et al., 2014; Forbester et al., 2015; Hill and Spence, 2017).”
Self-citationThorne, C. A., Chen, I. W., Sanman, L. E., Cobb, M. H., Wu, L. F., & Altschuler, S. J. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.024 · Cited by 165 · see citing works
“…have become increasingly powerful platforms for understanding tissue organization, modeling disease, and identifying novel therapeutics (Boj et al., 2015; Gao et al., 2014; Lancaster et al., 2013; McCracken et al., 2014; Ootani et al., 2009; Warmflash et al., 2014; van de Wetering et al., 2015).”
BackgroundHelicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models
Burkitt, M. D., Duckworth, C. A., Williams, J. M., & Pritchard, D. M. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.027649 · Cited by 178 · see citing works
“Since these discoveries, several groups have established gastric organoid systems using slightly different approaches (McCracken et al., 2014; VanDussen et al., 2015), as described below.”
BackgroundInfluentialStem Cell Heterogeneity and Plasticity in Epithelia
Donati, G., & Watt, F. M. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.04.014 · Cited by 169 · see citing works
Patient-derived organoids in precision cancer medicine
Tong, L., Cui, W., Zhang, B., Fonseca, P., Zhao, Q. C., Zhang, P., Xu, B., Zhang, Q., Li, Z., Seashore-Ludlow, B. A., et al. (2024) · Med · doi:10.1016/j.medj.2024.08.010 · Cited by 173 · see citing works
Kidney organoids: accurate models or fortunate accidentsPreprint
Little, M. H., & Combes, A. N. (2019) · Genes & Development · doi:10.1101/gad.329573.119 · Cited by 164 · see citing works
“The organotypic self-organization of cells within differentiating human pluripotent stem cell (hPSC) cultures to form what are now referred to as “organoids” (Lancaster and Knoblich 2014) has provided researchers with complex multicellular models of developing human tissues including optic cup, intestine, cerebral cor…”
BackgroundGut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities
Pandey, H., Tang, D. W. T., Wong, S. H., & Lal, D. (2023) · Cancers · doi:10.3390/cancers15030866 · Cited by 165 · see citing works
Patient-derived induced pluripotent stem cells in cancer research and precision oncology
Papapetrou, E. P. (2016) · Nature Medicine · doi:10.1038/nm.4238 · Cited by 159 · see citing works
Organoid cultures for cancer modeling
Yan, H. H. N., Chan, A., Lai, F. P.-L., & Leung, S. Y. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.05.012 · Cited by 163 · see citing works
Stomach development, stem cells and disease
Kim, T.-H., & Shivdasani, R. A. (2016) · Development · doi:10.1242/dev.124891 · Cited by 175 · see citing works
“(A) After promoting the differentiation of pluripotent human stem cells (iPSCs or ESCs) to definitive endoderm with Activin A, antral organoids are established by further treatment with Wnt, FGF4, RA, Noggin and EGF (McCracken et al., 2014).”
BackgroundInfluentialInnovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing
Bédard, P., Gauvin, S., Ferland, K., Caneparo, C., Pellerin, È., Chabaud, S., & Bolduc, S. (2020) · Bioengineering · doi:10.3390/bioengineering7030115 · Cited by 160 · see citing works
Barrila, J., Crabbé, A., Yang, J., Franco, K., Nydam, S. D., Forsyth, R. J., Davis, R. R., Gangaraju, S., Ott, C. M., Coyne, C. B., et al. (2018) · Infection and Immunity · doi:10.1128/iai.00282-18 · Cited by 159 · see citing works
Concise Review: Current Status of Three-Dimensional Organoids as Preclinical Models
Kaushik, G., Ponnusamy, M. P., & Batra, S. K. (2018) · Stem Cells · doi:10.1002/stem.2852 · Cited by 156 · see citing works
Perspective: The promise of multi-cellular engineered living systems
Kamm, R. D., Bashir, R., Arora, N., Dar, R. D., Gillette, M. U., Griffith, L. G., Kemp, M. L., Kinlaw, K., Levin, M. G., Martin, A. C., et al. (2018) · APL Bioengineering · doi:10.1063/1.5038337 · Cited by 152 · see citing works
Trisno, S. L., Philo, K. E. D., McCracken, K. W., Catá, E. M., Ruiz-Torres, S., Rankin, S. A., Han, L., Nasr, T., Chaturvedi, P., Rothenberg, M. E., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.08.008 · Cited by 156 · see citing works
“Four days of RA treatment is also known to posteriorize foregut spheroids (McCracken et al., 2014), and loss of RA signaling results in abnormal development of posterior foregut organs (Bayha et al.”
BackgroundSelf-citation
- 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 › Surgery › 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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