Human gastric multi-regional assembloids for functional parietal maturation and patient-specific modelling of antral foveolar hyperplasia

Abstract Patient-derived human organoids have the capacity to self-organize into more complex structures. However, to what extent gastric organoids can recapitulate differentiated cell types and mucosal functions remains unexplored. Here we report on how region-specific gastric organoids can self-assemble into complex multi-regional assembloids. These assembloids show increased complexity and cross-communication between different gastric regions, allowing for the emergence of the elusive parietal cell type that is responsible for the production of gastric acid and shows a functional response to drugs targeting the H + /K + ATPase pump. We generate assembloids from paediatric patients with a genetic condition found to be associated with unusual antral foveolar hyperplasia and hyperplastic polyposis. Our multi-regional assembloid efficiently recapitulates hyperplastic-like antral regions, with decreased mucin secretion and glycosylated H + /K + ATPase subunit beta, which results in impaired gastric acid secretion. Multi-regional gastric assembloids, generated using paediatric-stem-cell-derived organoids, successfully recapitulate the structural and functional characteristics of the human stomach, offering a promising tool for studying gastric epithelial interactions and disease mechanisms that were previously challenging to investigate in primary models.