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Wnt Regulates Cellular Differentiation and Retinoid Metabolism Genes in the Mouse Stomach

ABSTRACT: Background & Aims: While recognized as a key regulator of gastrointestinal tissues, Wnt function in the stomach is poorly understood. This study aimed to define Wnt functions and identify Wnt-regulated genes in the stomach. Methods: Wnt signaling was localized using reporter mice. Proliferation was studied after canonical Wnt inhibition in vivo using Sox2-CreERT2; Ctnnb1fl/fl mice and in vitro using gastric organoid cultures. Wnt-regulated genes and potential effector pathways were identified by bulk RNAseq analysis of corpus and antral organoids 24 hours after Wnt inhibition. Retinoid metabolic components were localized in control and Wnt-inhibited mouse stomach by immunostaining. Results: Wnt signaling cells mapped to the base and proliferative region in both corpus and antrum. Wnt inhibition in vivo reduced proliferation and led to gastric stem cell loss. Cell signature analysis of RNAseq data revealed that gastric organoids adopt a surface cell transcriptional profile following Wnt inhibition instead of a basal cell profile. Furthermore, retinoid metabolism terms were differentially expressed after Wnt inhibition, with both corpus and antrum displaying decreased expression of retinoic acid target genes. Immunostaining mouse stomach showed differential localization of retinoid metabolic components in luminal pit cells (ALDH3A1), and basal chief/deep mucous cells (STRA6), with expression changes after b-catenin deletion consistent with the organoid analysis. Conclusion: Wnt signaling is required for gastric stem cell survival and promotes differentiation of cell types at the gland base. Retinoid metabolism is a candidate Wnt-regulated pathway, with cell-specific expression of key components. Localization of the retinol transporter STRA6 to high-Wnt cells at the gland base suggests that they are retinoic acid signaling cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE314919 | GEO | 2025/12/29

REPOSITORIES: GEO

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Project description:The glandular stomach is comprised of two anatomically and functionally distinct epithelial tissues termed corpus and antrum. While these compartments continuously regenerate to ensure normal organ function, our understanding of the molecular and cellular determinants that maintain these tissues remains incomplete. Here, we established an unbiased account of all gastric epithelial cells of the mouse corpus and antrum using single cell RNA-sequencing, allowing us to compare these adjacent epithelia and their stem cell compartments. Our data reveals that epithelial cell types with equivalent functional roles in the corpus and antrum utilize similar transcriptional programs, and our results support the existence of two discernible stem cell populations within the gland base and isthmus regions of these tissues. To study isthmus stem cells, typically underrepresented in conventional, gland base-enriched organoid cultures, we developed a novel 2D monolayer culture system to propagate mouse and human gastric epithelia. These 2D cultures expand indefinitely via Lgr5- isthmus-like cells and maintain the ability to differentiate into diverse gastric cell types. While 2D corpus and antrum cultures were transcriptionally similar, they retained a molecular memory and differentiation bias that mirrored their tissue of origin. Furthermore, gastric 2D cultures could be readily and reversibly converted into conventional 3D organoids, highlighting the remarkable plasticity of undifferentiated stomach epithelial cells. Finally, we utilized the 2D culture system to show that rare primary epithelial cells with high levels of Sox2 expression, previously hypothesized to be gastric stem cells, most closely resembled enterochromaffin (EC) cells and Sox2 is both necessary and sufficient to generate EC cells in vivo. Together, our data (i) provide important insights into the basis of gastric epithelial regeneration and differentiation, (ii) establish a tractable 2D culture system to capture and manipulate primary gastric isthmus stem cells in vitro and (iii) uncover a role for the stem cell factor Sox2 during EC cell specification.

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Wnt Regulates Cellular Differentiation and Retinoid Metabolism Genes in the Mouse Stomach

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