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Endocrinology. 2015 Nov;156(11):3924-36. doi: 10.1210/en.2015-1301. Epub 2015 Aug 4.

A Transcriptome-Led Exploration of Molecular Mechanisms Regulating Somatostatin-Producing D-Cells in the Gastric Epithelium.

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Metabolic Research Laboratories (A.A., B.Y.H.L., L.B., K.S., F.R., F.G.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and Pharma Research and Early Development (S.S.), Roche Innovation Center Basel, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.


The stomach epithelium contains a myriad of enteroendocrine cells that modulate a range of physiological functions, including postprandial secretion of regulatory peptides, gastric motility, and nutrient absorption. Somatostatin (SST)-producing D-cells are present in the oxyntic and pyloric regions of the stomach, and provide a tonic inhibitory tone that regulates activity of neighboring enteroendocrine cells and gastric acid secretion. Cellular mechanisms underlying the effects of regulatory factors on gastric D-cells are poorly defined due to problems in identifying primary D-cells, and uncertainty remains about which stimuli influence D-cells directly. In this study, we introduce a transgenic mouse line, SST-Cre, which upon crossing with Cre reporter strains, facilitates the identification and purification of gastric D-cells, or cell-specific expression of genetically encoded calcium indicators. Populations of D-cells from the gastric antrum and corpus were isolated and analyzed by RNA sequencing and quantitative RT-PCR. The expression of hormones, hormone receptors, neurotransmitter receptors, and nutrient receptors was quantified. Pyy, Gipr, Chrm4, Calcrl, Taar1, and Casr were identified as genes that are highly enriched in D-cells compared with SST-negative cells. Hormone secretion assays performed in mixed gastric epithelial cultures confirmed that SST secretion is regulated by incretin hormones, cholecystokinin, acetylcholine, vasoactive intestinal polypeptide, calcitonin gene-related polypeptide, oligopetides, and trace amines. Cholecystokinin and oligopeptides elicited increases in intracellular calcium in single-cell imaging experiments performed using cultured D-cells. Our data provide the first transcriptomic analysis and functional characterization of gastric D-cells, and identify regulatory pathways that underlie the direct detection of stimuli by this cell type.

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