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MRNA expression from wild type and gp130F/F mice antrum at 4 weeks of age in specific pathogen free (SPF) and germ free (GF) conditions

ABSTRACT: The role of microbe in promoting the initiation of gastric cancer (GC), the third most lethal cancer worldwide, are ill-defined. Here, we found that tumor size and weight in gp130F/F mouse stomach at condition were significantly reduced compared to those of at SPF condition. To investigate the underlying mechanism and how host genes were regulated in the presence/absence of microbe, arrays were performed in stomach tissue from gp130F/F and WT at 4 week old at SPF and GF conditions. The onset of gastric inflammation-associated adenomatous hyperplasia in gp130F/F mice occurs at ~6 weeks of age, with established intestinal-type tumors (3 months of age) progressively growing until a maximum size is reached at 6 months of age, with some evidence of carcinoma in situ. Since this phenotype histologically mimics early stage human GC, we therefore utilized gp130F/F mice as a model to identify miRNAs involved in the initiating molecular events leading to early stage GC. For this purpose, we performed miRNA microarrays on mouse gastric antrum tissue from gp130F/F and sex-matched littermate wild-type (gp130+/+) control mice aged 4 weeks; this age was chosen since antrum tissue from 4 week old (wo) gp130F/F mice is devoid of any histological signs of inflammation or hyperplasia, and is thus comparable to wild-type gastric antrum tissue.

ORGANISM(S): Mus musculus

PROVIDER: GSE93173 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA360232

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.

Project description:Transcription factor Foxq1 controls mucin gene expression and granule content in mouse stomach surface mucous cells ; Background and Aims: The gastric mucosa provides a stringent epithelial barrier and produces acid and enzymes that initiate digestion. In this regenerating tissue, progenitors differentiate continually into 4 principal specialized cell types, yet underlying mechanisms of differentiation are poorly understood. We identified stomach-restricted expression of the forkhead transcription factor FOXQ1. Methods: We used a combination of genetic, histochemical, ultrastructural and molecular analysis to study gastric cell lineages with respect to FOXQ1. Results: Within the developing and adult gastrointestinal tract, Foxq1 mRNA is restricted to the stomach, expressed prominently in foveolar (pit) cells, the abundant mucin-producing cells that line the mucosal surface, and required for their complete differentiation. Mice carrying Foxq1 coding mutations show virtual absence of mRNA and protein for the backbone of the predominant stomach mucin, MUC5AC. These observations correspond to a paucity of foveolar-cell secretory vesicles and notable loss of stomach but not intestinal mucus. Transcriptional profiling identified a surprisingly restricted set of genes with altered expression in Foxq1 mutant stomachs. MUC5AC is a highly tissue-restricted product that similarly depends on FOXQ1 in its other major site of expression, conjunctival goblet cells. Conclusions: Taken together, these observations imply that promotion of gastric MUC5AC synthesis is a primary, cell-autonomous function of FOXQ1. This study is the first to implicate a transcription factor in terminal differentiation of foveolar cells and begins to define the requirements to assemble highly specialized organelles and cells in the gastric mucosa. DOI: 10.1053/j.gastro.2008.04.019 Experiment Overall Design: RNA from stomach antrum from 2 of each Satin, Beige, and BL6 mice were compared using microarray analysis.

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MRNA expression from wild type and gp130F/F mice antrum at 4 weeks of age in specific pathogen free (SPF) and germ free (GF) conditions

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