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Human Multi-Regional Gastric Assembloids Favour Epithelial Cell Differentiation and Functional Parietal Maturation [paediatric patients]

ABSTRACT: Patient-derived human organoids have the remarkable capacity to self-organise into more complex structures. However, to which extend the gastric organoids can recapitulate the human stomach functions remains unexplored. Here, we report how gastric region-specific organoids can self-assemble into complex multi-regional assembloids showing levels of differentiation unattainable with simpler models. The assembloid shows preserved fundus, body and antrum regionality and gastric-specific crosstalk pathways arise. Remarkably, the increased complexity and cross communication between the different gastric regions, allows for the arise of the elusive parietal cell type, responsible for the production of gastric acid, the essential function for food digestion. We showed functional response to drugs targeting ATPase H+/K+ and further maturation of the assembloid when transplanted in vivo. This advanced in vitro model, using patient-derived tissue-specific progenitors, successfully recapitulates the structural and functional characteristics of the human stomach, offering a promising strategy for studying developmental processes, tissue interactions, and disease mechanisms that were previously challenging to attain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280843 | GEO | 2025/04/23

REPOSITORIES: GEO

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Project description:We previously established long-term 3D organoid culture systems for several murine tissues (intestine, stomach, pancreas and liver) as well as human intestine and pancreas. Here, we describe culture conditions to generate long-term 3D culture from human gastric stem cells. The technology can be applied to study the epithelial response to infection with Helicobacter pylori. Human gastric cultures can expand indefinitely in 3D Matrigel. Cultures can be generated from normal tissue, from single sorted stem cells, or from tumor tissue. Organoids maintain many characteristics of the respective tissue in terms of histology, marker expression and euploidy. Organoids from normal tissue express markers of four lineages of the stomach and self-organize in gland and pit-domains. They can be directed to specifically express either lineages of the gastric gland, or the gastric pit by addition of Nicotinamide and withdrawal of Wnt. While gastric pit lineages react marginally to bacterial infection, gastric gland lineages mount a strong inflammatory response. The gastric culture system provides a unique tool to study gastric pathologies. We generated 2 sets of experiments. The first set contains organoids in 4 conditions: (1) organoids in expansion condition ENRWFGNiTi ("gland-type organoids") from 3 donors, (2) organoids as in 1 but differentiated for 4 days in differentiation condition ENR_FGNiTi ("pit'type organoids"), (3) organoids as in 1 but infected with Helicobacter pylori strain P12 MOI 50 for 2 h, (4) organoids as in 2 but infected as in 3. All 4 conditions were tested on the same organoid line in parallel. This experiment was conducted independently with cultures from 3 different donors. The second set of experiments compares freshly isolated glands with organoids. Samples from 2 patients were analyzed. Each patient received a total gastrectomy. From each patient, glands from corpus region or pyloric antrum were isolated. From each isolation, one aliquod was stored for microarray analysis and one aliquod used to generate organoids. Organoids and glands were subsequently lysed and analyzed in parallel.

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Human Multi-Regional Gastric Assembloids Favour Epithelial Cell Differentiation and Functional Parietal Maturation [paediatric patients]

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