Characteristics of gastrin controlled ECL cell specific gene expression☆
Introduction
Gastrin is the main regulator of gastric acid secretion and oxyntic mucosal growth. In the stomach, gastrin receptors are found mainly on ECL cells [1], [2], [3], [4], [5], [6] and to a lesser extent on stem cells [7] and parietal cells [2], [8]. Thus, the ECL cells are the primary target for gastrin, mediating many of its actions (for review, see Ref. [9]).
Gastrin stimulates the ECL cells to secrete histamine, which in turn stimulates the parietal cells to produce acid. Gastrin regulates the expression of several genes in the ECL cells, such as histidine decarboxylase (HDC) [10], vesicular monoamine transporter 2 (VMAT2) [11] and chromogranin A [12], [13]. In addition gastrin stimulates the growth of the ECL cells [9], [14], [15], [16] and of the oxyntic mucosa [14], [17]. However, it is not known whether the growth-promoting effects of gastrin reflect the direct stimulation of stem cells [6], [7] or whether it is mediated by growth factors released from the ECL cells [18]. Knowledge about gastrin controlled gene expression in the ECL cells is therefore crucial for our understanding of gastric physiology.
Studies of the gastrin control of gene expression are often conducted on cell lines (see for instance Refs. [19], [20]). However, such in vitro models may not reproduce the events in the intact cell. The microarray technology allows a global analysis of the gene expression profile of any cell population. We have now applied this technique to purified ECL cell preparations from fasted rats (hypogastrinemia) and omeprazole-treated rats (hypergastrinemia) in an attempt to identify the genes that are characteristically expressed by ECL cells and to determine which of these operate under gastrin control.
Section snippets
ECL cell isolation, RNA extraction and expression profiling
Twelve male Sprague–Dawley rats (200–250 g) were kept in two groups of six. Hypergastrinemia was induced in one group by giving omeprazole (Astra-Zeneca, Mölndal, Sweden), 400 μmol kg− 1, by gastric gavage twice daily for two days as described previously [15]. The other rats were fasted for 24 h (free access to water). The rats were sacrificed by exsanguinations (under CO2) between 8:00 and 10:00 in the morning (1–2 h after the last dose of omeprazole). The stomachs were removed and the ECL
Principal component analysis
The principal component analysis organizes the data according to the variation in gene expression. The analysis identified three different categories. The biggest difference in gene expression was between the fundic and antral biopsies (squares) on one hand and the ECL cells (from fasted (circles) or omeprazole-treated rats (stars)) on the other (1st dimension) (Fig. 1). Hence, ECL cell gene expression is indeed different from gene expression in fundic and antral biopsies. In the 2nd dimension
Discussion
This study uses isolated and highly purified rat stomach ECL cells to demonstrate that ECL cells characteristically express genes that encode proteins involved in RNA synthesis and translation as well as synthesis of proteins involved in either secretion or secretion-related metabolic activities. These features enable the ECL cells to synthesize, store and secrete histamine, peptides and proteins in substantial amounts (for review, see Ref. [9]). Interestingly, also proteins responsible for the
Acknowledgements
The skillful technical assistance of Susanne Smed and Bo Lindberg is greatly appreciated. The work was supported by the Novo Nordic Foundation. Thomas Hansen is thanked for fruitful discussions.
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The work was supported by the Novo Nordic Foundation.