The role of gastrin and extracellular matrix proteins in proliferation and differentiation of gastric epithelial cells

Abstract: The mechanisms regulating the proliferation and differentiation processes that give rise to and maintain the gastric epithelium have not yet been completely elucidated.In the present studies, in vitro models were established and the influence of growth factors and extracellular matrix proteins on these processes were investigated. Pentagastrin and hydrocortisone were found to accelerate the development of H,KTPase-positive parietal cells and other epithelial cells from undifferentiated gastric epithelial cells of foetal rats. These undifferentiated cells and also presumably immature epithelial cells in the progenitor zone of adult gastric glands were shown to express cholecystokinin-2 (CCK2) receptors and are therefore targets for the trophic action of gastrin.H,K-ATPase-positive parietal cells in the progenitor zone of adult glands were also found to express CCK2 receptors, indicating that gastrin may stimulate maturation of the parietal cell lineage even during adult life. Parietal cells located in the upper region of the glandular unit are probably responsible for most of the acid secretion, because these cells were found to express the membrane-cytoskeletallinker ezrin, reported to be present in the canaliculi of stimulated parietal cells.Pulse-labelling with 5-bromo-2'-deoxyuridine showed that during the gestational period, when the main motphological conformations and maturation of the gastric epithelium occur, proliferating cells appear at the basal epithelial cell layer and migrate towards the gastric lumen. This indicates that epithelial-mesenchymal cell and cell-matrix interactions may be involved in regulation of the cell proliferation and differentiation. Investigation of the expression of extracellular matrix proteins in foetal rat stomachs revealed a marked increase in collagen type I, suggesting that collagen, which is known to stimulate epithelial cell proliferation, is involved in the initial folding of the embryonic epithelium and formation of glandular structures.In experiments in vitro, development of mucus-producing cells from undifferentiated gastric epithelial cells was stimulated by collagens but inhibited by fibronectin and laminin. In adult gastric epithelium, collagen type I was present only in the pit region of the glandular unit, where surface mucous cells are located. Thus, collagen type I, which is overexpressed in gastric ulcers and gastric cancers, likely stimulates proliferation of mucus-producing cells.In conclusion, expression of CCK2 receptors was detected in foetal gastric epithelium and in the progenitor zone of adult gastric epithelium, implying that gastrin exerts trophic effects on immature gastric epithelial cells, during both stomach organogenesis and adult life. The spatial and temporal expression of extracellular matrix proteins and the effects of these proteins on development of mucus-producing cells in vitro indicate that extracellular matrix proteins may play an important role in regulation of epithelial cell proliferation and differentiation, and thus in the maintenance of normal cellular composition and function ofthe gastric epithelium.