Antral Endocrine Cells Research Articles

Reprogrammed Stomach Tissue as a Renewable Source of Functional β Cells for Blood Glucose Regulation

The gastrointestinal (GI) epithelium is a highly regenerative tissue with the potential to provide a renewable source of insulin(+) cells after undergoing cellular reprogramming. Here, we show that cells of the antral stomach have a previously unappreciated propensity for conversion into functional insulin-secreting cells. Native antral endocrine cells share a surprising degree of transcriptional similarity with pancreatic β cells, and expression of β cell reprogramming factors in vivo converts antral cells efficiently into insulin(+) cells with close molecular and functional similarity to β cells. Induced GI insulin(+) cells can suppress hyperglycemia in a diabetic mouse model for at least 6 months and regenerate rapidly after ablation. Reprogramming of antral stomach cells assembled into bioengineered mini-organs in vitro yielded transplantable units that also suppressed hyperglycemia in diabetic mice, highlighting the potential for development of engineered stomach tissues as a renewable source of functional β cells for glycemic control.

Stomach antral endocrine cells in patients with irritable bowel syndrome.

To the best of our knowledge, stomach antral endocrine cells have not previously been investigated in patients with irritable bowel syndrome (IBS). Thus, in the present study, 76 patients with IBS were examined (designated as IBS-total). Diarrhoea was the predominant symptom in 26 of these patients (IBS-D), while in 21 patients, the predominant symptoms were both diarrhoea and constipation (IBS-M) and in 29 patients the predominant symptom was constipation (IBS-C). Forty-three healthy subjects were enrolled as the controls. Stomach antral biopsy samples obtained from all of the subjects were immunostained using the avidin-biotin-complex method for serotonin, gastrin, somatostatin and serotonin transporter (SERT). The immunopositive cell densities and immunoreactivity intensities were determined by computer-aided image analysis. The density of the serotonin-immunoreactive cells was significantly decreased in the IBS-M patients and increased in the IBS-C patients relative to the controls. The immunoreactivity intensity did not differ significantly between the controls and IBS-total. The density of the gastrin-immunoreactive cells was significantly greater in the IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensity of gastrin was significantly greater in the IBS-D patients than in the controls. The density of the somatostatin-immunoreactive cells cells was significantly lower in the IBS-total, IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensities of both somatostatin and SERT did not differ significantly between the controls and IBS-total. The increase in gastrin cell density and the decrease in somatostatin cell density in all IBS subtypes may cause high levels of gastric secretion, which may in turn contribute to the high incidence of dyspepsia and gastro-oesophageal reflux observed in patients with IBS.

Effects of unilateral cervical vagotomy on antral endocrine cells in mouse.

The present study was carried out to investigate the effect of unilateral cervical vagotomy on the antral endocrine cells in mouse. Fifty-four mice were randomly divided into three groups, 18 in each, for left or right cervical vagotomy, or sham operation as controls. The animals were sacrificed 2, 4, and 8 weeks after the operation, respectively. Chromogranin-, gastrin/CCK-, serotonin-, and somatostatin-cells were detected by immunohistochemistry and quantitated by computerised image analysis. The results showed that the number of chromogranin-cells was decreased in both left and right vagotomized mice after 4 weeks and remained at the same level after 8 weeks. The numbers of gastrin-, serotonin- and somatostatin-cells did not change after right vagotomy. However, the numbers of gastrin- and somatostatin-cells were decreased after left vagotomy, whereas no change was found in serotonin-cells. Endocrine cells with vacuolated cytoplasm and pyknotic nuclei were also observed during the course of time. The alteration in the antral endocrine cells observed in this study seemed to be dynamic and depended on the observation time after the operation as well as the denervated branches of the vagus nerve. This may explain, at least partially the contradictory results obtained earlier by different investigators.

Tu1833 Ingestion of a High Fat Diet Sensed by Primary Cilia Lowers Gastrin Secretion

Background:We have recently demonstrated that the presentation of primary cilia on gastric endocrine cells is regulated by food intake. A cilia-deficient mousemodel resulted in increased gastrin mRNA and hypergastrinemia, suggesting the presence of cilia is tightly linked to gastrin production. It has been shown in different organs that cilia dysfunction results in loss of sensory signaling, and obesity is characteristic of two ciliopathies, Bardet-Biedl syndrome and Alstrom. Therefore we tested the hypothesis that antral cilia can discriminate between standard and high fat diets. Methods: We analyzed C57BL/6J mice (wild type) fed with standard (Control, Lab Diet 5L0D) or High Fat (Research Diets Inc., D12492) chow. Mice were starved overnight and then allowed free access to food for 0.5, 1, 1.5, 2, 4 h and overnight (16 h). The amount of food ingested and emptied was determined by weighing the stomachs at time of euthanasia. Gastric acidity was measured by titration of gastric content and gastrin levels by ELISA. Cilia were visualized by immunohistochemistry for acetylated-tubulin then the number of cilia per gland (cpg) was quantified by morphometric analysis. Results: In mice fed Control chow (n=8), the maximum amount of food ingested was achieved by 1 h, gastric contents decreased by 4 h, and gastric acidity peaked at 2 h. The number of antral cilia decreased 45% over 1.5 h and then recovered by 4 h (Fig. 1A). Maximum circulating gastrin levels (3.5 fold increase) occurred by 2 h (Fig.1B). The stomach content, gastric acidity, gastrin levels, and cilia numbers did not change after 4 h of food intake. When mice were fed High Fat chow (n=6), the maximum amount of food ingested was achieved by 1 h and did not decrease for the entire 16 h of the experiment. Gastric acidity increased with High Fat intake, but in contrast with Control chow, remained elevated. The number of antral cilia varied slightly by 2 h then decreased only after 4 h (Fig.1A). Plasma gastrin levels increased 2 fold with High Fat during the first hour (Fig. 1B). However, gastrin levels did not increase further and did not reach the same level than with Control chow. Gastrin levels inversely correlated with antral cilia numbers with both chow diets. The number of cilia in the corpus was not different between the two diets. Conclusion: A high fat diet sensed by cilia on antral endocrine cells regulates gastrin release and thus the gastric response to food intake including acid secretion.

Tu1834 Orexins Exert a PRO-Apoptotic Effect on Digestive Human Neuroendocrine Tumors (NET) in an Ex-Vivo Culture Model of Tissue Slices

Background:We have recently demonstrated that the presentation of primary cilia on gastric endocrine cells is regulated by food intake. A cilia-deficient mousemodel resulted in increased gastrin mRNA and hypergastrinemia, suggesting the presence of cilia is tightly linked to gastrin production. It has been shown in different organs that cilia dysfunction results in loss of sensory signaling, and obesity is characteristic of two ciliopathies, Bardet-Biedl syndrome and Alstrom. Therefore we tested the hypothesis that antral cilia can discriminate between standard and high fat diets. Methods: We analyzed C57BL/6J mice (wild type) fed with standard (Control, Lab Diet 5L0D) or High Fat (Research Diets Inc., D12492) chow. Mice were starved overnight and then allowed free access to food for 0.5, 1, 1.5, 2, 4 h and overnight (16 h). The amount of food ingested and emptied was determined by weighing the stomachs at time of euthanasia. Gastric acidity was measured by titration of gastric content and gastrin levels by ELISA. Cilia were visualized by immunohistochemistry for acetylated-tubulin then the number of cilia per gland (cpg) was quantified by morphometric analysis. Results: In mice fed Control chow (n=8), the maximum amount of food ingested was achieved by 1 h, gastric contents decreased by 4 h, and gastric acidity peaked at 2 h. The number of antral cilia decreased 45% over 1.5 h and then recovered by 4 h (Fig. 1A). Maximum circulating gastrin levels (3.5 fold increase) occurred by 2 h (Fig.1B). The stomach content, gastric acidity, gastrin levels, and cilia numbers did not change after 4 h of food intake. When mice were fed High Fat chow (n=6), the maximum amount of food ingested was achieved by 1 h and did not decrease for the entire 16 h of the experiment. Gastric acidity increased with High Fat intake, but in contrast with Control chow, remained elevated. The number of antral cilia varied slightly by 2 h then decreased only after 4 h (Fig.1A). Plasma gastrin levels increased 2 fold with High Fat during the first hour (Fig. 1B). However, gastrin levels did not increase further and did not reach the same level than with Control chow. Gastrin levels inversely correlated with antral cilia numbers with both chow diets. The number of cilia in the corpus was not different between the two diets. Conclusion: A high fat diet sensed by cilia on antral endocrine cells regulates gastrin release and thus the gastric response to food intake including acid secretion.

Effect of intragastric ammonia on gastrin-, somatostatin- and somatostatin receptor subtype 2 positive-cells in rat antral mucosa

Somatostatin suppresses gastrin and somatostatin secretion via somatostatin receptors (SSTRs). Ammonia produced by Helicobacter pylori has been reported to modify gastric gastrin and somatostatin levels. We investigated the distribution of SSTR-subtype 2 (SSTR-2) in relation to gastrin- and somatostatin-containing cells and the effect of ammonia solution (0.01%–0.1%) administered orally for 2 to 4 weeks on these cells in rat antral mucosa by immunohistochemistry. The majority of SSTR-2 peptide [31–41]-positive cells were located in the basal third of the glands. Double staining experiments revealed that SSTR-2 peptide [31–41]-positive cells are co-localized in 85.0 ± 2.2% of the gastrin-containing cells and in 34.4 ± 4.8% of the somatostatin-containing cells. Ammonia solution significantly decreased the number of somatostatin-containing cells and increased the proportion of SSTR-2 peptide [31–41]-labeling in the somatostatin-containing cells in a duration-dependent manner. Maximum changes were observed in rats treated with ammonia solution at the lowest level of 0.01% accompanied by an increase in serum gastrin levels in the portal vein. Sodium hydroxide at the similar pH to 0.01% ammonia solution had no effect. These findings suggest that SSTR-2 are localized in antral endocrine cells and that ammonia solution mainly decreases somatostatin-containing cells without SSTR-2 expression, resulting in an increase in gastrin secretion into the portal vein.

Age-related changes in antral endocrine cells in mice.

Antral endocrine cells in four age groups of mice, namely prepubertal (1 month old), young (3 months old), ageing (12 months old) and senescent (24 months old), were detected by immunocytochemistry and quantified by computerized image analysis. A statistical difference was detected between the different age groups regarding the numbers of gastrin-, somatostatin-, and serotonin-immunoreactive cells. The number of gastrin-immunoreactive cells significantly increased between 1 and 12 months, whereas they became significantly fewer between 12 and 24 months. Somatostatin-immunoreactive cell number increased significantly in 1-, 12- and 24-month-old mice, compared with young mice (3 months old). The number of serotonin-immunoreactive cells also increased significantly in 1- and 12-month-old mice as compared with young mice. There was a statistical difference between different age-groups regarding the cell secretory index (CSI) of somatostatin- and gastrin-immunoreactive cells, the CSI of both somatostatin- and serotonin-immunoreactive cells increased significantly in 1-, 12-, and 24-month-old mice, compared with young mice. There was no statistical difference between the different age-groups regarding the CSI of gastrin-immunoreactive cells, nor between males and females regarding the number and CSI of all the endocrine cell types investigated. It is suggested that the large number of somatostatin-immunoreactive cells in ageing and senescent mice might have an impact on the gastric delay seen in the elderly. It was concluded also that the changes in the antral endocrine cells could be involved in the development of dysfunction of the gastrointestinal tract inherent in ageing, or could be secondary to structural and functional changes in the alimentary tract caused by ageing.

Antral endocrine cells in nonobese diabetic mice.

The antral endocrine cells were investigated in nonobese diabetic (NOD) mice by means of immunohistochemistry, image analysis, and radioimmunoassays (RIA). As controls BALB/CJ mice of the same age and sex as the NOD mice were used. The number of gastrin- and somatostatin-immunoreactive cells was significantly decreased in both prediabetic and diabetic mice. There was no statistical difference between the NOD mice and controls regarding the serotonin-immunoreactive cells. Somatostatin levels as revealed by RIA in the antrum of both prediabetic and diabetic NOD mice were lower than those of the controls. There was no statistical difference in the level of antral gastrin between NOD mice and the controls. It was concluded that the changes in antral cells are primary to the onset of diabetes, and that the abnormalities observed in the antral cells in an animal model for diabetes type I might have relevance for the upper gastrointestinal dysfunction displayed in human diabetes.

Ultrastructural changes in antral endocrine cells in Helicobacter pylori (HP) gastritis : V.K. Sharma, [formula omitted], W.G. Linscheer, R. Oates. Veterans Affairs Medical Center and SUNY Health Science Center, Syracuse, NY

Ultrastructural changes in antral endocrine cells in Helicobacter pylori (HP) gastritis : V.K. Sharma, [formula omitted], W.G. Linscheer, R. Oates. Veterans Affairs Medical Center and SUNY Health Science Center, Syracuse, NY

The changes of antral endocrine cells in Helicobacter pylori infection

The changes of antral endocrine cells in Helicobacter pylori infection

Heterogeneity of chromogranin A-derived peptides in bovine gut, pancreas and adrenal medulla

Chromogranin A is produced in many endocrine cell types, and is widely used as a marker in endocrine-cell pathology and secretory-cell biology. There is some evidence that it may be proteolytically processed to yield the putative pancreatic regulatory peptide, pancreastatin, and, in order to characterize the relevant pathways in gastrointestinal and pancreatic endocrine cells, we have used, in radioimmunoassay, site-directed antibodies to pancreastatin itself (L331) and to a sequence of chromogranin A immediately C-terminal to pancreastatin (L300). The latter antibody revealed three major forms of immunoreactivity of 8 kDa and five peptides of approx. 3 kDa in bovine pancreas and gut extracts. The 8 kDa peptides were characterized as chromogranin A-(248-313)-peptides, i.e. C-terminally extended forms of pancreastatin; two of the 8 kDa variants differed in two positions, confirming a polymorphism predicted from cDNA sequencing. One of the 3 kDa peptides was characterized as chromogranin A-(297-313)-peptide, i.e. the C-terminal heptadecapeptide of the 8 kDa peptide that would be liberated after cleavage to yield pancreastatin. On the basis of chromatographic studies, immunohistochemistry and the stoichiometry of different immunoreactive peptides, three different pathways of chromogranin A processing were identified: in adrenal chromaffin cells chromogranin A existed mainly as the unmodified intact protein, in pancreatic islet and gastric antral endocrine cells pancreastatin and the 3 kDa peptides were major products, but in small intestine and gastric corpus endocrine cells there was little nor no pancreastatin and the 8 kDa cleavage product predominated. There are therefore important differences in the distribution of chromogranin A-derived peptides between quite closely related populations of endocrine cells that are attributable not only to variable post-translational cleavage but also to the expression of different primary sequences. It seems possible that in different cell types chromogranin A-derived peptides might subserve a variety of different functions.

The antral gastrin-producing cells in duodenal ulcer patients. A light microscopic and ultrastructural study during long-term, low dose treatment with cimetidine.

The antral mucosa has been examined in four duodenal ulcer patients before and during long-term, low dose treatment with cimetidine (given a total dose of between 472 g and 894 g). No convincing changes were found in the number or the volume of G cells. Signs of inactivity were demonstrated ultrastructurally, with small granules of intermediate type, a reduced amount of granular endoplasmatic reticulum and Golgi complex, mostly showing no signs of granulogenesis. The occurrence of bundles of cytoplasmic microfilaments, not observed before treatment and the reduced number of D cells may also be signs of inactivity. Hyperplasia and/or neoplasia were not seen in other antral endocrine cells.

Aldehyde-fuchsin staining of antral endocrine cells.

Correlative studies have been made to identify the endocrine cells stained by Aldehyde-Fuchsin (AF) in the cat and human antral mucosa. D-cells weakly stained by AF after oxidation: this staining might be related to the disulphide group present in the molecule of Somatostatin (the hypothalamic hormone recently localized in D-cells). The gastrin-producing G-cells were on the contrary strongly stained (without oxidation) in tissues fixed in Helly-fluid. Histochemical investigations on the mechanism of such staining lead to the conclusion that it might be related to affinity of the stain for hidden acidic groups.