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

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2015 Aug 5

PMID 26241122

Citations 41

Authors

Alice Adriaenssens

Brian Yee Hong Lam

Lawrence Billing

Katie Skeffington

Sabine Sewing

Frank Reimann

Fiona Gribble

Affiliations

Soon will be listed here.

Abstract

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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References

Skare S, Hanssen K, Kriz V, Torjesen P . Arginine infusion increases peripheral plasma somatostatin in man. Clin Endocrinol (Oxf). 1984; 21(3):299-308. DOI: 10.1111/j.1365-2265.1984.tb03473.x. View

Giraud A, Soll A, Cuttitta F, Walsh J . Bombesin stimulation of gastrin release from canine gastrin cells in primary culture. Am J Physiol. 1987; 252(3 Pt 1):G413-20. DOI: 10.1152/ajpgi.1987.252.3.G413. View

Dubois M . Immunoreactive somatostatin is present in discrete cells of the endocrine pancreas. Proc Natl Acad Sci U S A. 1975; 72(4):1340-3. PMC: 432529. DOI: 10.1073/pnas.72.4.1340. View

Sternini C, Wong H, Pham T, De Giorgio R, Miller L, Kuntz S . Expression of cholecystokinin A receptors in neurons innervating the rat stomach and intestine. Gastroenterology. 1999; 117(5):1136-46. DOI: 10.1016/s0016-5085(99)70399-9. View

Sachs G, Zeng N, Prinz C . Physiology of isolated gastric endocrine cells. Annu Rev Physiol. 1997; 59:243-56. DOI: 10.1146/annurev.physiol.59.1.243. View

Bunzow J, Sonders M, Arttamangkul S, Harrison L, Zhang G, Quigley D . Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001; 60(6):1181-8. DOI: 10.1124/mol.60.6.1181. View

Lloyd K, Maxwell V, Chuang C, Wong H, Soll A, Walsh J . Somatostatin is released in response to cholecystokinin by activation of type A CCK receptors. Peptides. 1994; 15(2):223-7. DOI: 10.1016/0196-9781(94)90006-x. View

Luche H, Weber O, Rao T, Blum C, Fehling H . Faithful activation of an extra-bright red fluorescent protein in "knock-in" Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol. 2006; 37(1):43-53. DOI: 10.1002/eji.200636745. View

Diakogiannaki E, Pais R, Tolhurst G, Parker H, Horscroft J, Rauscher B . Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor. Diabetologia. 2013; 56(12):2688-96. PMC: 3825574. DOI: 10.1007/s00125-013-3037-3. View

10.

Sugano K, Park J, Soll A, Yamada T . Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture. J Clin Invest. 1987; 79(3):935-42. PMC: 424241. DOI: 10.1172/JCI112904. View

11.

Vigna S, Giraud A, Mantyh P, Soll A, Walsh J . Characterization of bombesin receptors on canine antral gastrin cells. Peptides. 1990; 11(2):259-64. DOI: 10.1016/0196-9781(90)90079-k. View

12.

Wahren J . Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. Lancet. 1976; 2(7997):1213-6. DOI: 10.1016/s0140-6736(76)91142-9. View

13.

Chayvialle J, DESCOS F, Bernard C, Martin A, Barbe C, Partensky C . Somatostatin in mucosa of stomach and duodenum in gastroduodenal disease. Gastroenterology. 1978; 75(1):13-9. View

14.

Goldberg D, Walesky M, Sherwin R . Effect of somatostatin on the plasma amino acid response to ingested protein in man. Metabolism. 1979; 28(8):866-73. DOI: 10.1016/0026-0495(79)90214-2. View

15.

Piqueras L, Tache Y, Martinez V . Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice. Br J Pharmacol. 2004; 142(1):67-78. PMC: 1574929. DOI: 10.1038/sj.bjp.0705739. View

16.

Marathe C, Rayner C, Jones K, Horowitz M . Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Exp Diabetes Res. 2011; 2011:279530. PMC: 3124003. DOI: 10.1155/2011/279530. View

17.

Yamada T, Soll A, Park J, Elashoff J . Autonomic regulation of somatostatin release: studies with primary cultures of canine fundic mucosal cells. Am J Physiol. 1984; 247(5 Pt 1):G567-73. DOI: 10.1152/ajpgi.1984.247.5.G567. View

18.

Habib A, Richards P, Cairns L, Rogers G, Bannon C, Parker H . Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology. 2012; 153(7):3054-65. PMC: 3440453. DOI: 10.1210/en.2011-2170. View

19.

Larsson L, Houggaard D . Evidence for paracrine somatostatinergic regulation of gastrin gene expression by double-staining cytochemistry and quantitation. J Histochem Cytochem. 1994; 42(1):37-40. DOI: 10.1177/42.1.7903328. View

20.

Morley J, Levine A, Yamada T, GEBHARD R, Prigge W, Shafer R . Effect of exorphins on gastrointestinal function, hormonal release, and appetite. Gastroenterology. 1983; 84(6):1517-23. View