Li Xia, Lin Feng, Cui Qiqi, Sun Shiyu, Li Shixin, Wang Yue, Wang Yiting, Bai Jianbo, Liu Shiyi, Guo Jia, Han Yizhao, Zhang Meiru, Chang Tie, Zheng Yifan, Liu Jianlin, Liu Longqi, Wang Leyun, Fu Jianping, Liu Xin, Bai Bing, Shao Yue
Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing, China.
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09508-8.
The human stomach features distinct, regionalized functionalities along the anterior-posterior axis. Historically, studies on stomach patterning have used animal models to identify the underlying principles. Recently, human pluripotent stem (hPS)-cell-based gastric organoids for modelling domain-specific development of the fundic and antral epithelium are emerging. However, recapitulating self-organized fundic-antral patterning in early stomach organogenesis remains challenging, presenting a considerable barrier for advancing knowledge of stomach organogenesis. Here we report human gastroids-a self-organized multilineage gastric organoid derived from hPS cells-to model gastric fundic-antral patterning in vitro. Through multi-germ-layer co-development, we generate gastroids that feature an epithelial chamber with bipolar fundic-antral patterning, annexed with neural populations near the fundic domain while enveloped by mesenchymal cells, therefore showing molecular, cellular, structural and anatomical similarity to stomach development in vivo. Non-endodermal cells, especially neural populations, function as a critical signalling centre to instruct fundic-antral patterning in gastroids through WNT-mediated crosstalk. Single-cell transcriptomic profiling and genetic silencing further reveal NR2F2 as a key mediator of fundic-antral patterning in gastroid development. This study reveals a principle for instructing gastric patterning and provides a higher-fidelity platform for advancing knowledge of stomach organogenesis and gastric organoid development.
人类胃沿前后轴具有独特的区域化功能。历史上，关于胃模式形成的研究一直使用动物模型来确定其潜在原理。最近，基于人类多能干细胞（hPS）的胃类器官用于模拟胃底和胃窦上皮的特定区域发育的研究正在兴起。然而，在早期胃器官发生过程中重现自组织的胃底-胃窦模式仍然具有挑战性，这对推进胃器官发生知识构成了相当大的障碍。在此，我们报告了人类胃状体——一种源自hPS细胞的自组织多谱系胃类器官——用于在体外模拟胃底-胃窦模式。通过多胚层共同发育，我们生成了胃状体，其特征是具有双极胃底-胃窦模式的上皮腔，在胃底区域附近伴有神经细胞群，同时被间充质细胞包裹，因此在分子、细胞、结构和解剖学上与体内胃发育相似。非内胚层细胞，尤其是神经细胞群，作为关键信号中心，通过WNT介导的串扰指导胃状体中的胃底-胃窦模式形成。单细胞转录组分析和基因沉默进一步揭示NR2F2是胃状体发育中胃底-胃窦模式形成的关键调节因子。这项研究揭示了指导胃模式形成的原理，并为推进胃器官发生和胃类器官发育的知识提供了一个更高保真度平台。
