Wnt/β-catenin promotes gastric fundus specification in mice and humans

Despite the global prevalence of gastric disease, there are few adequate models in which to study the fundus epithelium of the human stomach. We differentiated human pluripotent stem cells (hPSCs) into gastric organoids containing fundic epithelium by first identifying and then recapitulating key events in embryonic fundus development. We found that disruption of Wnt/β-catenin signalling in mouse embryos led to conversion of fundic to antral epithelium, and that β-catenin activation in hPSC-derived foregut progenitors promoted the development of human fundic-type gastric organoids (hFGOs). We then used hFGOs to identify temporally distinct roles for multiple signalling pathways in epithelial morphogenesis and differentiation of fundic cell types, including chief cells and functional parietal cells. hFGOs are a powerful model for studying the development of the human fundus and the molecular bases of human gastric physiology and pathophysiology, and also represent a new platform for drug discovery. Wnt signalling is shown to be required for specification of the gastric fundus in mice, and was used to develop human gastric organoids with functional fundic cell types. Human gastric fundus organoids Using a mouse model for stomach development, James Wells and colleagues have delineated the requirement of Wnt signalling for specification of the fundus region of the stomach in mammals—the upper part of the stomach close to the cardial notch and oesophagus. On the basis of this finding, the authors develop human gastric organoids derived from fundic pluripotent stem cells, which should provide a powerful model for the study of gastric physiology and pathophysiology, as well as for drug discovery.