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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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“…that resemble various tissues and organoids, such as the brain (Lancaster et al., 2013), eyes (Nakano et al., 2012), kidney (Takasato et al., 2014), lung (Dye et al., 2015), gastric tissue (McCracken et al., 2014) and intestine (Spence et al., 2011) have been already successfully generated (Fig.”
Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants
Varzideh, F., Pahlavan, S., Ansari, H., Halvaei, M., Sawa Kostin, D., Feiz, M.-S., Latifi, H., Aghdami, N., Braun, T. W., & Baharvand, H. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.11.033 · Cited by 97
Organoids of the female reproductive tract
Chumduri, C., & Turco, M. Y. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-020-02028-0 · Cited by 110
Yao, Q., Cheng, S., Pan, Q., Yu, J., Cao, G., Li, L., & Cao, H. (2024) · MedComm · doi:10.1002/mco2.735 · Cited by 100
Backert, S., & Tegtmeyer, N. (2017) · Toxins · doi:10.3390/toxins9040115 · Cited by 95
“pylori induced epithelial cell proliferation that correlated with c-Met phosphorylation as analyzed by immunoprecipitation and Western blotting [104,105].”
MethodHigh-throughput single-cell transcriptomics on organoids
Brazovskaja, A., Treutlein, B., & Camp, J. G. (2018) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2018.11.002 · Cited by 95
“Gut Gut organoids (stomach, small intestine, colon) can be established either from adult-derived intestinal epithelial stem cells [15,16] or through the differentiation of iPSCs through endoderm derived foregut and hindgut spheroids [17,18].”
BackgroundShih, H., Seymour, P. A., Patel, N., Xie, R., Wang, A., Liu, P. P., Yeo, G. W., Magnuson, M., & Sander, M. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.082 · Cited by 87
“Consistent with previous studies (McCracken et al., 2014), Cdx2 was largely absent from the pancreatic buds (Fig.”
Influential3d organ-on-a-chip: the convergence of microphysiological systems and organoids
Baptista, L. S., Porrini, C., Kronemberger, G. S., Kelly, D. J., & Perrault, C. M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1043117 · Cited by 90
Generating human intestinal tissues from pluripotent stem cells to study development and disease
Sinagoga, K. L., & Wells, J. M. (2015) · The EMBO Journal · doi:10.15252/embj.201490686 · Cited by 95
“For example, it has been shown that organoids can be injected with bacteria and this can be used to study early disease inductive events (McCracken et al , 2014).”
Self-citationTranscriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A
Hoàng, C., Hale, M. A., Azevedo-Pouly, A., Elsässer, H., Deering, T. G., Willet, S. G., Pan, F. C., Magnuson, M., Wright, C., Swift, G. H., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00358-16 · Cited by 87
“SOX9 is in cells of the neck region (45, 46) that overlap GSII-stained mucous cells and a subset of Ki67-positive progenitor cells of the isthmus (47).”
BackgroundQu, S., Xu, R., Yi, G., Li, Z., Zhang, H., Qi, S., & Huang, G. (2024) · Molecular Biomedicine · doi:10.1186/s43556-023-00165-9 · Cited by 106
“Kyle W McCracken et al. reported the modelling human development and disease in pluripotent stem-cell-derived gastric organoids [175].”
BackgroundThree-dimensional cell culture: from evolution to revolution
Alhaque, S., Themis, M., & Rashidi, H. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2017.0216 · Cited by 92
Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents
Wang, Y. B., de Lartigue, G., & Page, A. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00643 · Cited by 96
Development and application of human adult stem or progenitor cell organoids
Rookmaaker, M. B., Schutgens, F., Verhaar, M. C., & Clevers, H. C. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.118 · Cited by 91
Experimental study of tuberculosis: From animal models to complex cell systems and organoids
Fonseca, K. L., Rodrigues, P., Olsson, I. A. S., & Saraiva, M. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006421 · Cited by 90
“The potential of organoids to study infectious processes has been increasingly demonstrated in many original papers and recently reviewed by Mills and Estes [71], with most examples coming from human gastric [72], brain [73, 74], and gut [75, 76] organoids.”
BackgroundA xenogeneic-free system generating functional human gut organoids from pluripotent stem cells
Uchida, H., Machida, M., Miura, T., Kawasaki, T., Okazaki, T., Sasaki, K., Sakamoto, S., Ohuchi, N., Kasahara, M., Umezawa, A., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.86492 · Cited by 90
“Recently, it was reported that PSCs or isolated tissue progenitors could be induced to generate intestine-like 3-dimensional “organoids” (9–11).”
BackgroundThe safety of human pluripotent stem cells in clinical treatment
Simonson, O. E., Domogatskaya, A., Volchkov, P., & Rodin, S. (2015) · Annals of Medicine · doi:10.3109/07853890.2015.1051579 · Cited by 91
Generating human antral and fundic gastric organoids from pluripotent stem cells
Broda, T. R., McCracken, K., & Wells, J. M. (2018) · Nature Protocols · doi:10.1038/s41596-018-0080-z · Cited by 81
Self-citationYavitt, F. M., Brown, T. E., Hushka, E. A., Brown, M. E., Gjorevski, N., Dempsey, P. J., Lütolf, M. P., & Anseth, K. S. (2020) · Advanced Materials · doi:10.1002/adma.201905366 · Cited by 89
Zheng, F., Xiao, Y., Liu, H., Fan, Y., & Dao, M. (2021) · Advanced Biology · doi:10.1002/adbi.202000024 · Cited by 96
Gastrointestinal Organoids: Understanding the Molecular Basis of the Host–Microbe Interface
Hill, D. R., & Spence, J. R. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.11.007 · Cited by 90
Self-citationAssessing Toxicity with Human Cell-Based In Vitro Methods
Zink, D., Chuah, J. K. C., & Ying, J. Y. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.01.008 · Cited by 87
Organoid-based Models to Study the Role of Host-microbiota Interactions in IBD
Poletti, M., Arnauts, K., Ferrante, M., & Korcsmáros, T. (2020) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjaa257 · Cited by 93
Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases
Blutt, S. E., Crawford, S. E., Ramani, S., Zou, W. Y., & Estes, M. K. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.12.001 · Cited by 86
Proposed Molecular and miRNA Classification of Gastric Cancer
Alessandrini, L., Manchi, M., Re, V. D., Dolcetti, R., & Canzonieri, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061683 · Cited by 86
BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract
Zhang, Y., & Que, J. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034500 · Cited by 91
SARS-CoV-2 infection and replication in human gastric organoids
Giobbe, G. G., Bonfante, F., Jones, B. C., Gagliano, O., Luni, C., Zambaiti, E., Perin, S., Laterza, C., Busslinger, G. A., Stuart, H. T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26762-2 · Cited by 86
Organoids as Models for Neoplastic Transformation
Neal, J. T., & Kuo, C. J. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044249 · Cited by 85
Cho, S., Yoon, C., Lee, J. H., Chang, K. K., Lin, J.-X., Kim, Y.-H., Kook, M., Aksoy, B. A., Park, D. J., Ashktorab, H., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1679 · Cited by 85
“Tumor-derived organoids are an in vitro model that can recapitulate the pathophysiology of the original tumors along with preserving cellular heterogeneity and self-renewal capacity (36).”
BackgroundRetractedWang, Q., Chen, C., Xu, X., Shu, C., Cao, C., Wang, Z., Fu, Y. S., Xu, L., Xu, K., Xu, J., et al. (2022) · Advanced Science · doi:10.1002/advs.202201889 · Cited by 83
Zhang, R., Koido, M., Tadokoro, T., Ouchi, R., Matsuno, T., Ueno, Y., Sekine, K., Takebe, T., & Taniguchi, H. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.01.006 · Cited by 82
“5) in mice and day 20 in human stem cell culture (McCracken et al., 2014), and this process primarily contributes to the formation of the small and large intestines in adults (Wells and Melton, 1999).”
BackgroundInfluentialHepatocyte growth factor in physiology and infectious diseases
Imamura, R., & Matsumoto, K. (2017) · Cytokine · doi:10.1016/j.cyto.2016.12.025 · Cited by 82
“In addition, McCracken et al. recently developed a de novo generation of three-dimensional human gastric organoids in vitro via the directed differentiation of human pluripotent stem cells [94].”
Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword
Mentis, A. A., Boziki, M. K., Grigoriadis, N., & Papavassiliou, A. G. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03044-1 · Cited by 81
Calderon-Gierszal, E. L., & Prins, G. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0133238 · Cited by 81
“Recently, advancements in stem cell biology have permitted directed differentiation of embryonic stem cells (ESCs) into a variety of organoids entirely in vitro thus providing robust models that provide unparalleled insight into the developmental processes of many organs [36, 37].”
Background
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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