Topographic distribution pattern of morphologically different G cells in the murine antral mucosa.

Gastrin-secreting enteroendocrine cells (G cells) in the antrum play an important role in the regulation of gastric secretion, gastric motility and mucosal cell proliferation. Recently we have uncovered the existence of two subpopulations of G cells with pivotally different morphology and a distinct localization in the antral invaginations; the functional implications of the different G cell types are still elusive. In this study a transgenic mouse line in which EGFP is expressed under the control of a gastrin promoter was used to elucidate the distribution pattern of the two G cell types throughout the different regions of the antrum. The results of immunohistochemical analyses revealed that G cells were not equally distributed along the anterior/posterior axis of the antrum. The "typical" pyramidal- or roundish-shaped G cells, which are located in the basal region of the antral invaginations, were more abundant in the proximal antrum bordering the corpus region but less frequent in the distal antrum bordering the pylorus. In contrast, the "atypical" G cells, which are located in the upper part of the antral invaginations and have a spindle-like contour with long processes, were evenly distributed along the anterior/posterior axis. This characteristic topographic segregation supports the notion that the two G cell types may serve different functions. A comparison of the antrum specific G cells with the two pan-gastrointestinal enteroendocrine cell types, somatostatin-secreting D cells and serotonin-secreting enterochromaffin (EC) cells, revealed a rather similar distribution pattern of G and D cells, but a fundamentally different distribution of EC cells. These observations suggest that distinct mechanisms govern the spatial segregation of enteroendocrine cells in the antrum mucosa.

Requirement of the tissue-restricted homeodomain transcription factor Nkx6.3 in differentiation of gastrin-producing G cells in the stomach antrum.

Many homeodomain transcription factors function in organogenesis and cell differentiation. The Nkx family illustrates these functions especially well, and the Nkx6 subfamily controls differentiation in the central nervous system and pancreas. Nkx6.3, a recent addition to this subfamily, overlaps Nkx6.1 and Nkx6.2 in expression in the hindbrain and stomach. Nkx6.3 transcripts localize in the epithelium of the most distal stomach region, the antrum and pylorus; expression in the adult intestine is lower and confined to the proximal duodenum. Nkx6.3(-)(/)(-) mice develop and grow normally, with a grossly intact stomach and duodenum. These mice show markedly reduced gastrin mRNA, many fewer gastrin-producing (G) cells in the stomach antrum, hypogastrinemia, and increased stomach luminal pH, with a corresponding increase in somatostatin mRNA levels and antral somatostatin-producing (D) cells. They express normal levels of other transcription factors required for gastric endocrine cell differentiation, Pdx1, Pax6, and Ngn3; conversely, Ngn3(-)(/)(-) mice, which also show reduced gastrin levels, express Nkx6.3 normally. These studies implicate Nkx6.3 as a selective regulator of G- and D-cell lineages, which are believed to derive from a common progenitor, and suggest that it operates in parallel with Ngn3.

Proliferation and functional changes of pancreatic gastrin cells in neonatal rat.

INTRODUCTION: Although gastrin cells are not found in the adult pancreas, they are found transiently in the neonatal pancreas. It has been suggested that gastrin may play a role in pancreatic development. However, cell kinetics as well as the fate and the role of gastrin cells are not clear. METHODOLOGY: Proliferation and functional changes of pancreatic gastrin cells in neonatal Wister rats were studied by immunohistochemistry and [(3)H]thymidine autoradiography. RESULTS: Numbers of pancreatic gastrin cells in neonatal rats showed a peak immediately after birth and then decreased rapidly. Gastrin cells were observed within approximately 2 weeks after birth in islets and within approximately 4 weeks after birth among exocrine cells. In contrast with the decrease of gastrin cell numbers, numbers of duodenal cholecystokinin cells increased remarkably after 7 days of age. Proliferative activity of acinar cells showed two peaks at age 2 days and 9 days. Despite a decrease in gastrin cell numbers, gastrin cells maintained a certain degree of proliferative activity. The "re-staining method" for gastrin and insulin revealed that immunoreactive cells for both gastrin and insulin were rarely found a few days after birth. CONCLUSION: These results suggest that pancreatic gastrin cells do not die off or change to another type of endocrine cell and that some gastrin cells change to insulin cells.

Effect of a histamine H1 receptor antagonist on gastric endocrine cell proliferation induced by chronic acid suppression in rats.

The effect of histamine on gastrin cells and enterochromaffin-like cells has not yet been clarified. We investigated the influence of pyrilamine (a histamine H1 receptor antagonist) on serum gastrin level, gastrin cells, and enterochromaffin-like cells in rats with or without 4 weeks of famotidine treatment. The rats were divided into six groups: a control group, two pyrilamine groups (2mg/kg, or 20mg/kg, p.o.), a famotidine group (20mg/kg twice/daily i.m.), and two pyrilamine + famotidine groups. The serum gastrin concentration was determined, and gastrin cells and enterochromaffin-like cells were identified by the labeled streptavidin biotin complex method and counted. Hypergastrinemia, gastrin cell hyperplasia, and enterochromaffin-like cell hyperplasia were found after 4 weeks of famotidine treatment. Four weeks of treatment with pyrilamine alone did not affect the gastrin level, gastrin cells, or enterochromaffin-like cells in the rat stomach. When combined with famotidine, pyrilamine enhanced famotidine-induced hypergastrinemia, but it did not affect gastrin cell hyperplasia, and it significantly inhibited enterochromaffin-like cell hyperplasia. These results suggest that gastrin secretion and enterochromaffin-like cell proliferation may be regulated by histamine via the H1 receptor during acid suppression.

Immunocytochemical evidence suggesting that diamine oxidase catalyzes biosynthesis of gamma-aminobutyric acid in antropyloric gastrin cells.

gamma-Aminobutyric acid (GABA) is a neurotransmitter that also occurs in a few non-neuronal cell types, where it may serve as a paracrine modulator. GABA is biosynthesized from glutamate by glutamate decarboxylase (GAD) and from putrescine via diamine oxidase (DAO). GAD is demonstrable in several GABA-positive cell types but is undetectable in the GABA-containing gastrin cells and somatostatin cells of the antropyloric mucosa of the stomach. Using two antisera raised against synthetic peptides corresponding to two different regions of rat DAO, we now demonstrate strong reactivity for DAO in gastrin-positive cells of the rat antropyloric mucosa, whereas somatostatin-positive cells as well as other structures of the antrum are unreactive. Western blotting analysis of antrum and colon demonstrate that both antisera react with a single band of 85 kD, consistent with the predicted molecular weight of DAO. Expression of DAO mRNA in the antrum is demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR). Our results strongly indicate that gastrin cells produce GABA via DAO-catalyzed oxidation of putrescine, and experimental data moreover suggest that the biosynthesis of GABA is regulated by the prandial state. Because GABA modulates release of somatostatin, these results point to a new mechanism of paracrine interaction between gastrin cells and somatostatin cells.

Gastrinaemia and G-cell density in the antral gastrocystoplasty: an experimental study in rats.

OBJECTIVE: To evaluate gastrinaemia and G-cell density in the antrum incorporated into the bladder of rats after antrocystoplasty. Materials and methods Thirty-two adult, female Wistar EPM-1 rats (body weight 200-220 g) were divided into four equal groups that underwent; group 1, no treatment (controls); group 2, a sham operation; group 3, antrectomy; and group 4, antrocystoplasty. The rats were assessed 2 months after treatment, and gastrinaemia and the G-cell density determined in the antrum mucosa incorporated into the bladder. RESULTS: Compared with group 1, serum gastrin was significantly lower in group 3 (P<0.05) and the G-cell density lower in group 4 (P<0.05), although there was no decrease in gastrinaemia in group 4. CONCLUSION: Antrocystoplasty in rats did not affect gastrinaemia but reduced the number of G cells in the antrum incorporated into the bladder.

Ulex europaeus agglutinin-I binds to developing gastrin cells.

We have previously reported that antropyloric gastrin (G) and somatostatin (D) cells derive from precursor (G/D) cells that coexpress both hormones. We have now analyzed this endocrine cell pedigree for binding of Ulex europaeus agglutinin-I (UEA-I), which previously has been reported to represent a useful marker for cell differentiation. Subpopulations of G/D, D, and G cells were all found to express UEA-I binding. Labelling with bromodeoxyuridine showed that UEA-I positive G cells possessed a higher labelling index than UEA-I negative G cells. These data suggest that the UEA-I positive G cells represent maturing cells still involved in DNA synthesis and cell division. Electron microscopically, specific UEA-I binding sites were localized to the secretory granules and the apical cell membrane of G cells. We conclude that UEA-I represents a differentiation marker for G cells. Moreover, the presence of UEA-I binding sites in these cells may be relevant for Helicobacter pylori-mediated disturbances of gastric acid secretion and gastrin hypersecretion.

Effects of enprostil on gastric endocrine secretion during chronic administration of lansoprazole.

We investigated changes in the secretory kinetics of gastric endocrine cells related to the administration of lansoprazole, and the effects of enprostil on these altered kinetics. Male Wistar-derived 8-week-old rats were allotted to a control group, a lansoprazole administration group, an enprostil administration group, and a lansoprazole + enprostil administration group. Lansoprazole (30 mg/kg once a day for 4 weeks) and enprostil (10 micrograms/kg twice a day for 4 weeks) were administered into the gastric lumen with a gastric tube. At this time, blood was collected and immunohistological staining of gastric endocrine cells was conducted to investigate the secretory kinetics. Lansoprazole administration induced hypergastrinemia, increase of gastrin cells, and increase of enterochromaffin-like cells. Enprostil administration induced increase of somatostatin cells. The group administered lansoprazole + enprostil exhibited significant decreases in serum gastrin level, total gastrin cell count, and total enterochromaffin-like cell count, compared with the group administered lansoprazole alone. These findings suggest that enprostil may ameliorate the alteration in gastric endocrine secretion produced by the chronic administration of lansoprazole.