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

By K. McCracken, Emily M. Catá, Calyn M. Crawford, Katie L. Sinagoga, Michael A. Schumacher, Briana E. Rockich, Y. Tsai, C. Mayhew, J. Spence, Y. Zavros and 1 more. Nature, 2014

900 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/b1653ba0968557d6f661d99b0feace29ee893da8

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In Genetics

1. Hans Clevers
2. R. Nusse
3. Pengfei Lu

In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. James M. Wells
4. Elaine Fuchs
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In Surgery

1. Hans Clevers
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Citations in the corpus

• Modeling Development and Disease with Organoids. (2016, methodology): “In another example, human stomach organoids, grown from PSCs or aSCs, can be productively infected by Helicobacter pylori (Bartfeld et al., 2015; McCracken et al., 2014).”
• In vitro generation of human pluripotent stem cell derived lung organoids (2015, background): “Using this approach, differentiation of hPSCs into lung lineages has been achieved using diverse methodology with varying degrees of success (Kadzik and Morrisey, 2012; Longmire et al., 2012; Mou et al., 2012; Wong et al., 2012; Ghaedi et al., 2013; Huang et al., 2013; Firth et al., 2014).”
• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “Thus, organoid protocols have been reported for mouse and human stomach (Barker et al., 2010; Bartfeld et al., 2015; McCracken et al., 2014), liver (Huch et al.”