Researchers have developed a new model of the human stomach that more accurately replicates both the structure and function of the organ compared with previous laboratory systems. By combining region-specific gastric organoids into multi-regional assembloids (MRAs), the team successfully recreated key features of the stomach, including functional acid-secreting parietal cells and region-to-region communication. This model provides a robust platform for researching gastric development, physiology, and disease processes that have been challenging to investigate using existing models.
The human stomach is classified into three regions, namely the fundus, body, and antrum, each with specialized cell types and functions. Effective communication between these regions is essential for normal digestion, especially for regulating the secretion of gastric acid. Nevertheless, previous gastric organoid models typically include epithelial cells from a single region and lack the complexity needed to simulate full stomach functionality. Standard human tissue-derived organoids also contain few or no functional parietal cells capable of secreting gastric acid through the H+/K+ ATPase pump.
In this study, researchers first produced organoids from paediatric gastric biopsies collected from the fundus, body, and antrum. These organoids retained region-specific identity, as demonstrated by region-selective markers like PDX1 in antral organoids and IRX3 in fundic and body organoids. Nonetheless, individual organoids exhibited limited maturation and contained only a restricted number of functional cell types, including parietal cells.
To overcome these limitations, the researchers developed a self-assembly approach in which organoids from different regions of the stomach were embedded in collagen I and cultured under floating conditions. Over more than 10 days, the organoids fused to form elongated, tube-like MRA aligned in a fundus-body-antrum sequence. These structures exhibited polarized epithelial layers, gland formation, and a continuous luminal space, closely resembling human gastric epithelium.
The molecular and transcriptomic studies indicated that MRAs were more differentiated than single-region organoids or the more simplified assembloids. The markers of stem cell LGR5 decreased, whereas the markers of epithelial maturation increased. Notably, cross-talk pathways involving NOTCH, fibroblast growth factor, epidermal growth factor, and bone morphogenetic protein signalling were specific to MRAs, highlighting the role of regional interactions in promoting gastric maturation. MRAs also supported the differentiation of parietal cells. While parietal cell gene expression remained low at the RNA levels, protein analysis showed a marked increase in the H +/ K+ ATPase β-subunit expression, especially in the fundus and body regions. The glycosylated functional form of this protein is needed for acid secretion, which is more abundant in MRAs than in organoids or single-region assembloids. Functional assays confirmed that MRAs were actively secreted into gastric acid. Live imaging with acridine orange revealed that acid production increased in response to histamine and was inhibited by omeprazole, consistent with the physiological regulation of the gastric proton pump. Notably, this histamine-sensitive acid secretion was absent in simpler organoid systems.
The researchers further applied MRAs to model diseases using samples from pediatric patients with PMM2-associated hyperinsulinism, polycystic kidney disease, and inflammatory bowel disease. Patient-derived MRAs recapitulated disease phenotypes as well as antral foveolar hyperplasia phenotypes, decreased secretion of mucin, and impaired acid production, providing insights into disease pathology that are otherwise difficult to study in vivo.
Overall, this study demonstrates that multi-regional assemblies of human gastric assembloids can closely replicate the structure and function of the stomach. This platform offers a valuable tool for investigating gastric development, epithelial interactions, and specific stomach diseases in patients, as well as for testing drugs that target acid production.
Reference: Jones BC, Benedetti G, CalĂ G, et al. Human gastric multi-regional assembloids for functional parietal maturation and patient-specific modelling of antral foveolar hyperplasia. Nat Biomed Eng. 2026. doi:10.1038/s41551-025-01553-y
