EXPLORING GOBLET CELL-ENRICHED GASTRIC INTESTINAL METAPLASIA (GIM) ORGANOID CULTURE: A PLATFORM FOR THERAPEUTIC DRUG SCREENING

Gastric intestinal metaplasia (GIM) represents a precancerous lesion linked to an elevated risk of gastric carcinogenesis, presenting significant challenges in drug development due to the absence of suitable in vitro models. In this study, we engineered an in vitro GIM organoid model using normal human gastric organoids through genetic reprogramming and differentiation induction. The cells of the intestinal lineage were comprehensively characterized using single-cell sequencing, hematoxylin-eosin (H&E staining), Alcian Blue - Periodic Acid-Schiff (AB-PAS) staining, High Iron Diamine/Alcian Blue (HID-AB) staining, and immunofluorescence staining. Our findings reveal that the GIM organoids exhibit crypt-like structures under light microscopy, showcasing a goblet cell lineage expressing both intestinal acidic mucin and gastric neutral mucin. This phenotypic shift was associated with the down-regulation of the gastric marker MUC5AC and the up-regulation of intestinal markers MUC2 and TFF3. Intervention with Rebapatide significantly reduced the proportion of goblet cells in GIM organoids, concurrently leading to a decrease in the expression of MUC2 and TFF3. In conclusion, our study successfully establishes an in vitro culture that faithfully recapitulates the progression of GIM, achieving a histological transition from stomach to intestine. This implies that cells in GIM may derive from reprogrammed normal gastric stem cells. The developed model holds promise for advancing the development and screening of therapeutic agents tailored for the treatment of GIM.