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CCK2 receptors are necessary for the differentiation and proliferation of ECL cells in mouse and rat stomach

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Abstract

ECL cells in the oxyntic mucosa of the mouse and rat stomach express CCK2 receptors, which enable them to respond to gastrin by the production and release of histamine. We have studied CCK2 receptor-deficient mice and rats subjected to pharmacological CCK2 receptor blockade in an attempt to demonstrate the importance of gastrin signaling for ECL-cell differentiation and proliferation. In CCK2 receptor knockout mice, the ECL cells were replaced by a novel endocrine-like cell type lacking histamine and histidine decarboxylase but retaining pancreastatin and vesicle monoamine transporter type 2 (VMAT2). Ultrastructurally, they were characterized by the presence of small dense-core granules and microvesicles and by the absence of the secretory vesicles that are a hallmark feature of wild-type ECL cells. Upon pharmacological CCK2 receptor blockade, the ECL cells became small and inactive, although unchanged in number. By immunocytochemistry (histamine, pancreastatin and VMAT2) and electron microscopy (secretory vesicles) they remained recognizable as ECL cells; their proliferation in response to hypergastrinemia was prevented.

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REFERENCES

  • Bakke, I., Qvigstad, G., Sandvik, A. K., et al. (2001). The CCK-2 receptor is located on the ECL cell, but not on the parietal cell, Scand. J. Gastroenterol. 36, 1128–1133.

    Google Scholar 

  • Böttcher, G., Håkanson, R., Nilsson, G., et al. (1989). Effects of long-termhypergastrinaemia on the ultrastructure of enterochromaffin-like cells in the stomach of the rat, hamster and guinea pig, Cell Tissue Res. 256, 247–257.

    Google Scholar 

  • Canese, M. G. and Bussolati, G. (1977). Immuno-electron-cytochemical localization of the somatostatin cells in the human antral mucosa, J. Histochem. Cytochem. 25, 1111–1118.

    Google Scholar 

  • Chen, D., Nylander, A. G., Rehfeld, J. F., et al. (1993). Hypercholecystokininemia produced by pancreaticobiliary diversion causes gastrin-like effects on enterochromaffin-like cells in the stomach of rats subjected to portacaval shunting or antrectomy, Scand. J. Gastroenterol. 28, 988–992.

    Google Scholar 

  • Chen, D., Monstein, H. J., Nylander, A. G., et al. (1994). Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation, Gastroenterology 107, 18–27.

    Google Scholar 

  • Chen, D., Zhao, C. M., Andersson, K., et al. (1996a). Ultrastructure of enterochromaffi n-like cells in rat stomach: effects of alpha-fluoromethylhistidine-evoked histamine depletion and hypergastrinemia, Cell Tissue Res. 283, 469–478.

    Google Scholar 

  • Chen, D., Zhao, C. M., Nylander, A. G., et al. (1996b). Time course of hypertrophic and ultrastructural responses of rat stomach enterochromaffin-like cells to sustained hypergastrinemia, Cell Tissue Res. 284, 55–63.

    Google Scholar 

  • Chen, D., Zhao, C. M., Lindström, E., et al. (1999). Rat stomach ECL cells up-date of biology and physiology, Gen. Pharmacol. 32, 413–422.

    Google Scholar 

  • Chen, D., Zhao, C. M., Norlén, P., et al. (2000). Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells. A histochemical, electron-microscopic and chemical study, Cell Tissue Res. 299, 81–95.

    Google Scholar 

  • Chen, D., Zhao, C. M., Al-Haider, W., et al. (2002). Differentiation of gastric ECL cells is altered in CCK2 receptor-deficient mice, Gastroenterology 123, 577–585.

    Google Scholar 

  • Dartsch, C. and Persson, L. (1998). Recombinant expressionof rat histidinedecarboxylase: generation of antibodies useful for western blot analysis, Int. J. Biochem. Cell Biol. 30, 773–782.

    Google Scholar 

  • Dartsch, C., Sundler, F. and Persson, L. (1999). Antisera against rat recombinant histidine decarboxy-lase: immunocytochemical studies in different species, Histochem. J. 31, 507–514.

    Google Scholar 

  • De Giorgio, R., Su, D., Peter, D., et al. (1996). Vesicular monoamine transporter 2 expression in enteric neurons and enterochromaffin-like cells of the rat, Neurosci. Lett. 217, 77–80.

    Google Scholar 

  • Dornonville de la Cour, C., Björkqvist, M., Sandvik, A. K., et al. (2001). A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control, Regul. Pept. 99, 141–150.

    Google Scholar 

  • Facer, P., Bishop, A. E., Lloyd, R. V., et al. (1985). Chromogranin: a newly recognized marker for endocrine cells of the human gastrointestinal tract, Gastroenterology 89, 1366–1373.

    Google Scholar 

  • Friis-Hansen, L., Sundler, F., Li, Y., et al. (1998). Impaired gastric acid secretion in gastrin-defi cient mice, Am. J. Physiol. 274, G561–G568.

    Google Scholar 

  • Håkanson, R. and Owman, C. (1969). Argyrophilic reaction of histamine-containing epithelial cells in murine gastric mucosa, Experientia 25, 625–626.

    Google Scholar 

  • Håkanson, R. and Sundler, F. (1990). Proposed mechanism of induction of gastric carcinoids: the gastrin hypothesis, Eur. J. Clin. Invest. 20 (Suppl. 1), S65–S71.

    Google Scholar 

  • Håkanson, R. and Sundler, F. (1991). Histamine-producing cells in the stomach and their role in the regulation of acid secretion, Scand. J. Gastroenterol. Suppl. 180, 88–94.

    Google Scholar 

  • Håkanson, R., Böttcher, G., Ekblad, E., et al. (1986). Histamine in endocrine cells in the stomach. A survey of several species using a panel of histamine antibodies, Histochemistry 86, 5–17.

    Google Scholar 

  • Håkanson, R., Tielemans, Y., Chen, D., et al. (1993). Time-dependent changes in enterochromaffin-like cell kinetics in stomach of hypergastrinemic rats, Gastroenterology 105, 15–21.

    Google Scholar 

  • Håkanson, R., Chen, D. and Sundler, F. (1994). The ECL cells, in: Physiology of the Gastrointestinal Tract, L. R. Johnson (Ed.), Vol. 2, 3rd edn, pp. 1171–1184. Raven Press.

  • Havu, N. (1986). Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion, Digestion 35 (Suppl. 1), 42–55.

    Google Scholar 

  • Havu, N., Mattsson, H., Ekman, L., et al. (1990). Enterochromaffi n-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine, Digestion 45, 189–195.

    Google Scholar 

  • Helander, H. F., Wong, H., Poorkhalkali, N., et al. (1997). Immunohistochemical localization of gastrin/CCK-B receptors in the dog and guinea-pig stomach, Acta Physiol. Scand. 159, 313–320.

    Google Scholar 

  • Hohne-Zell, B., Galler, A., Schepp, W., et al. (1997). Functional importance of synaptobrevin and SNAP-25 during exocytosis of histamine by rat gastric enterochromaffin-like cells, Endocrinology 138, 5518–5526.

    Google Scholar 

  • Kidd, M., Modlin, I. M. and Tang, L. H. (1998). Gastrin and the enterochromaffin-like cell: an acid update, Dig. Surg. 15, 209–217.

    Google Scholar 

  • Kubota, H., Hayashi, H., Watanabe, T., et al. (1984). Mechanism of inactivation of mammalian L-histidine decarboxylase by (S)-alpha-fluoromethylhistidine, Biochem. Pharmacol. 33, 983–990.

    Google Scholar 

  • Langhans, N., Rindi, G., Chiu, M., et al. (1997). Abnormal gastric histology and decreased acid production in cholecystokinin-B/ gastrin receptor-defi cient mice, Gastroenterology 112, 280–286.

    Google Scholar 

  • Lindström, E., Björkqvist, M., Boketoft, A., et al. (1997). Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells, Regul. Pept. 71, 73–86.

    Google Scholar 

  • Lindström, E., Björkqvist, M. and Håkanson, R. (1999). Pharmacological analysis of CCK2 receptor antagonists using isolated rat stomach ECL cells, Br. J. Pharmacol. 127, 530–536.

    Google Scholar 

  • Lindström, E., Chen, D., Norlén, P., et al. (2001). Control of gastric acid secretion: the gastrin-ECL cell-parietal cell axis, Comp. Biochem. Physiol. A: Mol. Integr. Physiol. 128, 505–514.

    Google Scholar 

  • Nagata, A., Ito, M., Iwata, N., et al. (1996). G protein-coupled cholecystokinin-B/ gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo, Proc. Natl. Acad. Sci. USA 93, 11825–11830.

    Google Scholar 

  • Norlén, P., Curry, W. J., Björkqvist, M., et al. (2001). Cell-specific processing of chromogranin A in endocrine cells of the rat stomach, J. Histochem. Cytochem. 49, 9–18.

    Google Scholar 

  • Nylander, A. G., Chen, D., Lilja, I., et al. (1993). Enterochromaffin-like cells in rat stomach respond to short-terminfusion of high doses of cholecystokinin but not to long-term, sustained, moderate hyperCCKemia caused by continuous cholecystokinin infusion or pancreaticobiliary diversion, Scand. J. Gastroenterol. 28, 73–79.

    Google Scholar 

  • Pearse, A. G. and Bussolati, G. (1972). The identification of gastrin cells as G cells, Virchows Arch. A: Pathol. Pathol. Anat. 355, 99–104.

    Google Scholar 

  • Prinz, C., Kajimura, M., Scott, D. R., et al. (1993). Histamine secretion from rat enterochromaffinlike cells, Gastroenterology 105, 449–461.

    Google Scholar 

  • Rindi, G., Paolotti, D., Fiocca, R., et al. (2000). Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors, Virchows Arch. 436, 217–223.

    Google Scholar 

  • Ryberg, B., Tielemans, Y., Axelson, J., et al. (1990). Gastrin stimulates the self-replication rate of enterochromaffinlike cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats, Gastroenterology 99, 935–942.

    Google Scholar 

  • Solcia, E., Rindi, G., Buffa, R., et al. (2000). Gastric endocrine cells: types, function and growth, Regul. Pept. 93, 31–35.

    Google Scholar 

  • Tielemans, Y., Willems, G., Sundler, F., et al. (1990a). Self-replication of enterochromaffin-like cells in the mouse stomach, Digestion 45, 138–146.

    Google Scholar 

  • Tielemans, Y., Axelson, J., Sundler, F., et al. (1990). Serum gastrin concentration affects the self replication rate of the enterochromaffin-like cells in the rat stomach, Gut 31, 274–278.

    Google Scholar 

  • Tielemans, Y., Chen, D., Sundler, F., et al. (1992). Reversibility of the cell kinetic changes induced by omeprazole in the rat oxyntic mucosa. An autoradiographicstudy using tritiated thymidine, Scand. J. Gastroenterol. 27, 155–160.

    Google Scholar 

  • Wang, T. C., Dangler, C. A., Chen, D., et al. (2000). Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer, Gastroenterology 118, 36–47.

    Google Scholar 

  • Waldum, H. L., Sandvik, A. K., Brenna, E., et al. (1991). Gastrin-histaminesequence in the regulation of gastric acid secretion, Gut 32, 698–701.

    Google Scholar 

  • Zeng, N., Kang, T., Lyu, R. M., et al. (1998). The pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1-R) is expressed on gastric ECL cells: evidence by immunocytochemistry and RT-PCR, Ann. NY Acad. Sci. 865, 147–156.

    Google Scholar 

  • Zhao, C. M., Jacobsson, G., Chen, D., et al. (1997). Exocytotic proteins in enterochromaffin-like (ECL) cells of the rat stomach, Cell Tissue Res. 290, 539–551.

    Google Scholar 

  • Zhao, C. M., Chen, D., Andersson, K., et al. (1998). ECL cells of the rat stomach: development of lipofuscin in response to sustained gastrin stimulation, Cell Tissue Res. 291, 315–323.

    Google Scholar 

  • Zhao, C. M., Chen, D., Lintunen, M., et al. (1999a). Effects of reserpine on ECL-cell ultrastructure and histamine compartmentalizationin the rat stomach, Cell Tissue Res. 295, 131–140.

    Google Scholar 

  • Zhao, C. M., Chen, D., Lintunen, M., et al. (1999b). Secretory organelles in ECL cells of the rat stomach: an immunohistochemical and electron-microscopic study, Cell Tissue Res. 298, 457–470.

    Google Scholar 

  • Zhao, C. M., Bakke, I., Tostrup-Skogaker, N., et al. (2001). Functionally impaired, hypertrophic ECL cells accumulate vacuoles and lipofuscin bodies. An ultrastructural study of ECL cells isolated from hypergastrinemicrats, Cell Tissue Res. 303, 415–422.

    Google Scholar 

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Chen, D., Håkanson, R., Rehfeld, J.F. et al. CCK2 receptors are necessary for the differentiation and proliferation of ECL cells in mouse and rat stomach. Inflammopharmacology 10, 351–364 (2002). https://doi.org/10.1163/156856002321544828

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