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Modelling human development and disease in pluripotent stem-cell-derived gastric organoids
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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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Bioengineering Approaches for the Advanced Organoid Research
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Stem cell-derived organoids and their application for medical research and patient treatment
Bartfeld, S., & Clevers, H. C. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1531-7 · Cited by 226
“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 221
“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 208
Kim, W., Gwon, Y., Park, S., Kim, H., & Kim, J. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.03.039 · Cited by 216
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 225
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 222
“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
“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 211
“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 210
Organoid models of gastrointestinal cancers in basic and translational research
Lau, H. C.-H., Kranenburg, O., Xiao, H., & Yu, J. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0255-2 · Cited by 205
Collateral damage: Insights into bacterial mechanisms that predispose host cells to cancer
Gagnaire, A., Nadel, B., Raoult, D., Neefjes, J., & Gorvel, J.-P. (2017) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.171 · Cited by 189
Use and application of 3D-organoid technology
Artegiani, B., & Clevers, H. C. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy187 · Cited by 198
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 203
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
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 187
Organoid culture systems to study host–pathogen interactions
Dutta, D., & Clevers, H. C. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.07.012 · Cited by 192
“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. R. (2017) · Physiology · doi:10.1152/physiol.00041.2016 · Cited by 189
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 179
“…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 174
“…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 182
“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 175
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 192
Kidney organoids: accurate models or fortunate accidentsPreprint
Little, M. H., & Combes, A. N. (2019) · Genes & Development · doi:10.1101/gad.329573.119 · Cited by 163
“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 171
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 163
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 176
Stomach development, stem cells and disease
Kim, T.-H., & Shivdasani, R. A. (2016) · Development · doi:10.1242/dev.124891 · Cited by 175
“(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 167
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 163
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
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 155
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 152
“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
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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