McCracken Kyle W, Aihara Eitaro, Martin Baptiste, Crawford Calyn M, Broda Taylor, Treguier Julie, Zhang Xinghao, Shannon John M, Montrose Marshall H, Wells James M
Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Nature. 2017 Jan 12;541(7636):182-187. doi: 10.1038/nature21021. Epub 2017 Jan 4.
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.
尽管胃病在全球普遍存在，但用于研究人类胃底上皮的合适模型却很少。我们通过首先识别然后重现胚胎胃底发育中的关键事件，将人类多能干细胞（hPSCs）分化为含有胃底上皮的胃类器官。我们发现，小鼠胚胎中Wnt/β-连环蛋白信号通路的破坏导致胃底上皮向胃窦上皮的转化，并且hPSC衍生的前肠祖细胞中β-连环蛋白的激活促进了人类胃底型胃类器官（hFGOs）的发育。然后，我们使用hFGOs来确定多种信号通路在胃底细胞类型（包括主细胞和功能性壁细胞）的上皮形态发生和分化中的不同时间作用。hFGOs是研究人类胃底发育以及人类胃生理学和病理生理学分子基础的强大模型，也代表了一个新的药物发现平台。
