Letter | Published:

Modelling human development and disease in pluripotent stem-cell-derived gastric organoids

Nature volume 516, pages 400404 (18 December 2014) | Download Citation


Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world’s population and are largely due to chronic Helicobacter pylori infection1,2,3. Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis4, 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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Data deposits

The RNAseq data from hGOs have been deposited in ArrayExpress with accession number E-MTAB-2885.


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We thank A. Zorn, J. Whitsett, N. Shroyer, the Pluripotent Stem Cell Facility and members of the Wells and Zorn laboratories for reagents and feedback. We also thank M. Kofron for assistance with confocal imaging and T. Westbrook for providing the pInducer20 vector. We thank R. Peek for assistance with analysing electron micrograph images. This work was supported by National Institutes of Health grants R01DK080823, R01DK092456 and K01DK091415, NIGMS Medical Scientist Training Program T32 GM063483, and the American Gastroenterological Association: Robert and Sally Funderburg Research Award in Gastric Cancer. We also acknowledge core support from the Cincinnati Digestive Disease Center Award (P30 DK0789392), Clinical Translational Science Award (U54 RR025216), the Michigan Gastrointestinal Peptide Research Center (MGPRC; NIDDK 5P30DK034933), and technical support from CCHMC Confocal Imaging Core, CCHMC Pathology Core, and CCHMC Viral Vector Core.

Author information


  1. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA

    • Kyle W. McCracken
    • , Emily M. Catá
    • , Calyn M. Crawford
    • , Katie L. Sinagoga
    • , Christopher N. Mayhew
    •  & James M. Wells
  2. Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267, USA

    • Michael Schumacher
    •  & Yana Zavros
  3. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA

    • Briana E. Rockich
    •  & Jason R. Spence
  4. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA

    • Yu-Hwai Tsai
    •  & Jason R. Spence
  5. Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA

    • James M. Wells


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K.W.M. and J.M.W. conceived the study and experimental design, performed and analysed experiments and co-wrote the manuscript. Y.Z. designed, performed and helped analyse H. pylori experiments. E.M.C., C.M.C., K.L.S. and M.S. performed experiments. C.N.M. generated and characterized the iPS cell line. B.E.R., Y.-H.T. and J.R.S. designed, generated and characterized the LGR5-eGFP reporter hES cell line and performed RNA-seq experiments and analysis. All authors contributed to the writing or editing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yana Zavros or James M. Wells.

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