Role of gastrin in the development of gastric mucosa,ECL cells and A-like cells in newborn and young rats

Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK(2)) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 15-22 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but not before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point.We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK(2) receptor blockade is associated with a somewhat impaired development of the oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages.     

Immunocytochemical and ultrastructural characterization of endocrine cells in the larval stomach of the frog Rana temporaria tadpoles: a comparison with adult specimens

According to immunostaining and ultrastructural patterns, Rana temporaria tadpole stomach displays a well-differentiated endocrine population comprising, at least, six cellular types: ECL, EC [serotonin], D [somatostatin] - all three of them abundant -, P [bombesin] - less numerous -, CCK-8 [cholecystokinin/gastrin] and A [glucagon/glicentin] - both very scarce. Larval endocrine cells are mainly located in the surface epithelium and show open or closed morphologies. Cellular diversity is similar in tadpoles and frogs, with the exception of immunoreactivity for gastrin-17, found in adults in numerous cells. Larval cells display mature ultrastructural traits, although with smaller secretory granules. The different distribution of endocrine cells, which in adults are preferentially located in the glands, probably refers to different functional requirements. However, the rich vascular plexus present in larval mucosa may be an efficient transport medium of surface hormones to-gastric targets. The enhancement in adults of endocrine population and correlative increase in hormonal secretion indicates a more active functional role, probably related to the shift from herbivorous to carnivorous habits. In summary, the tadpole gastric endocrine population, although not as numerous as that of adult frogs, displays histological traits that indicate a relevant (immunoreactive and ultrastructural properties, cellular diversity) and specific (surface location, relative abundance of open-type cells) role of local regulatory factors in amphibian larval gastric function.     

Topography of somatostatin cells in the stomach of the rat: Possible functional significance

Summary Somatostatin cells in the stomach of the rat have a characteristic shape and distribution. In the antral mucosa they occur together with gastrin cells and enterochromaffin cells at the base of the glands. In the oxyntic mucosa they are scattered along the entire glands with some predominance in the zone of parietal cells. Throughout the gastric mucosa the somatostatin cells possess long and slender processes that emerge from the base of the cell and end in clublike swellings. Such processes appear to contact a certain proportion of neighbouring gastrin cells in the antral mucosa and parietal cells in the oxyntic mucosa.Exogenous somatostatin given by intravenous infusion to conscious rats counteracted the release of gastrin stimulated by feeding, elevated antral pH or vagal excitation. Gastrin causes parietal cells to secrete HCl and endocrine cells in the oxyntic mucosa to mobilise and synthesise histamine. Somatostatin is known to block the response of the parietal cells to gastrin. In contrast, somatostatin did not block the response of the histamine-storing endocrine cells to gastrin, perhaps because these endocrine cells lack receptors to somatostatin. Conceivably, somatostatin in the gastric mucosa has a paracrine mode of action. The observations of the present study suggest that somatostatin may affect some, but not all of the various cell types in the stomach. Under physiological conditions this selectivity may be achieved in the following ways: 1) Communication may be based on direct cell-to-cell contact. 2) Only certain cell types are supplied with somatostatin receptors.     

Hypergastrinaemia induced by acid blockade evokes enterochromaffin-like (ECL) cell hyperplasia in chicken,hamster and guinea-pig stomach

Summary Treatment of chickens, hamsters and guinea-pigs with large doses of the long-acting antisecretory agent omeprazole for 10 weeks resulted in elevated serum gastrin levels and in increased stomach weight and mass of oxyntic mucosa. Also the antral gastrin cell density was increased. Another striking effect was the hyperplasia of the histamine-producing enterochromaffin-like (ECL) cells — a prominent endocrine cell population with unknown function — in the oxyntic mucosa. Accordingly, the gastric mucosal histamine concentration and rate of histamine formation were increased in all three species. The results suggest that marked and long-lasting suppression of acid secretion leads to elevated serum gastrin levels and diffuse ECL cell hyperplasia not only in the rat, as previously seen, but also in the chicken, hamster and guinea-pig; this hyperplasia is associated with accelerated histamine formation in all three species. The following sequence of events is suggested to occur in mammalian as well as submammalian vertebrates: suppression of acid secretion — hypergastrinaemia — ECL cell hyperplasia.     

The distribution of endocrine cells in the mucosa of the gastrointestinal tract of the house musk shrew,Suncus murinus (Insectivora)

Summary The distribution of endocrine cells in the gastrointestinal tract of the house musk shrew, Suncus murinus (Family Soricidae, Order Insectivora) was studied immunohistochemically. The hormones investigated were gastrin, cholecystokinin (CCK), somatostatin, secretin, glucagon, gastric inhibitory polypeptide (GIP), motilin and neurotensin. In the gastric mucosa, gastrin and somatostatin cells were only found in the pyloric regions, and no other hormonal cell-types were observed. In the intestinal mucosa, the largest number of endocrine cells belonged to the gastrin and glucagon/glicentin cell-types, whereas CCK-33/39 and secretin cells were the least numerous. Numbers of other cell-types were intermediate between these two groups. The gastrin and GIP cells were mostly localized in the proximal portion of the intestine, decreasing in number towards the distal portion. The motilin and CCK-33/39 cells were restricted to the proximal half. The glucagon/glicentin and neurotensin cells were most abundant in the middle portion. The somatostatin and secretin cells, although only present in small numbers, were randomly distributed throughout the intestine. This characteristic distribution of gastrointestinal endocrine cells is discussed in comparison with the distribution patterns of other mammals.Dr. Munemitsu Hoshino, who was Professor of the Department of Pathology and directed this study, passed away on May 23rd 1988     

Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in rat stomach

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.     

Characteristics of gastrin controlled ECL cell specific gene expression

BACKGROUND: The ECL cells are histamine-producing endocrine cells in the oxyntic mucosa that synthesize and secrete proteins and peptides. They are the primary target for gastrin and mediate the control of gastrin on acid secretion and oxyntic mucosal growth. Knowledge of the molecular biology of the ECL cell is therefore important for understanding gastric physiology. Accordingly, we wanted to identify genes that are characteristically expressed in the ECL cells and controlled by gastrin. METHODS: Using Affymetrix GeneChips, RNA expression profiles were generated from ECL cells isolated by counterflow elutriation from hyper- or hypogastrinemic rats. Contamination from non-endocrine cells was eliminated by subtraction of the expression profiles of the fundic and antral mucosa. RESULTS: The expression of 365 genes was ECL cell characteristic. Gastrin was found to control the expression of 120 which could be divided into two major groups depending on the known or anticipated biological function of the encoded protein: genes encoding proteins involved in the secretory process and genes encoding proteins needed to generate energy for secretion. Interestingly, gastrin stimulation also increased ECL cells expression of anti-apoptotic genes. CONCLUSION: The ECL cell specific expression profile is reminiscent of that of neurons and other endocrine cells exhibiting high expression of genes encoding proteins involved in the synthesis, storage and secretion of neuropeptides or peptide hormones. Gastrin regulated the expression of one third of these genes and is thus involved in the control of secretion from the ECL cells.     

Stress-induced reduction of gastric acid in the rat is not associated with increased tissue somatostatin

In zero, mildly and severely stressed rats, gastric acid secretion, aortal and portal venous gastrin, venous glucagon and somatostatin in gastric, duodenal mucosa and in pancreas were examined. Serum gastrin and gastric acid secretion are reduced markedly by both kinds of stress, whereas plasma glucagon rises steadily with stress. As somatostatin in the tissues of stressed rats is not different from unstressed controls, gastrin and gastric acid reduction may not be attributed to an endocrine or paracrine action of somatostatin.