Expression of highly differentiated functions in gastric mucosal cells by paracrine mechanisms between distinct cell-types and appearance of adherent property to H. pylori in inverse proportion to decline in their differentiated functions

胃腺由至少11种不同的细胞类型组成，包括胃表面粘膜细胞（GSM）、壁细胞、主细胞和肠嗜铬样细胞（ECL）。它们的分化受多种生长因子调控，包括TGFa和TGFb、胃泌素以及细胞间或细胞间基质相互作用信号。通过以下四项研究，我们证明了高分化胃功能的表达需要形成每种细胞类型的功能定位。(1)胃泌素/CCK-B受体（CCKB-Rs）存在于壁细胞和ECL细胞上，而不存在于窝细胞上。然而，血清胃泌素水平与胃窝的生长密切相关。原位杂交结果显示，CGKB-R mRNA在高胃泌血症转基因小鼠粘膜中低腺区呈微弱分布。因此，胃泌素直接刺激窝细胞的生长。(2) Furin是一种蛋白质转化酶，分布在胃腺的上三分之一和下四分之一区域。我们鉴定上部furin阳性细胞为壁细胞，下部为主细胞。主要细胞表达TGFb的三种异构体，其激活需要furin的裂解。TGFa诱导原代培养的主细胞中furin和TGFb mrna的表达增加。(3) TGFa在窝细胞中高表达。TGFa可保护GSM细胞免于凋亡，并可增强Bcl-2的表达。这种抗凋亡作用是通过nf - kb依赖途径介导的。(4)钙蛋白酶是一种钙活化蛋白酶。我们发现四种钙蛋白酶异构体和钙蛋白酶抑制剂钙pastatin定位于不同的胃粘膜细胞类型。Calpastatin显著阻断细胞迁移能力。虽然我们不能通过腺体结构的下降来证明胃膜对幽门螺杆菌的强粘附性，但我们对容易受到幽门螺杆菌侵袭的复杂腺体结构提供了实质性的认识。少

The gastric gland is consists of at least 11 distinct cell-types, including gastric surface mucous (GSM) cells (=pit cells), parietal cells, chief cells, and enterochromaffin-like (ECL) cells. Their differentiation is regulated by a variety of growth factors including TGFa and TGFb, gastrin, and cell-to-cell or cell-to-matrix interaction signals. With the four studies below, we showed evidence that expression of highly differentiated gastric functions requires formation of functional localization of each cell-type.(1) Gastrin/CCK-B receptors (CCKB-Rs) are present on parietal and ECL cells, but not on pit cells. However, serum gastrin levels are well correlated with the growth of the gastric pit. In situ hybridization indicated that CGKB-R mRNA was faintly distributed along the mid-to low-glandular region in the hypergastrinemic transgenic mouse mucosa. Thus, gastrin directly stimulates the growth of the pit cells.(2) Furin, a proprotein-convertase, is distributed in the upper third lay … More er and the lower quarter region of the gastric gland. We identified the upper furin-positive cells as parietal cells and the lower cells as chief cells. Chief cells express three isoforms of TGFb, which requires cleavage by furin for its activation. TGFa induced an increase in the expression of furin and TGFb mRNAs in primary-cultured chief cells.(3) TGFa is highly expressed in the pit cells. TGFa protected GSM cells against apoptosis and enhanced the expression of Bcl-2. This antiapoptotic effect is mediated by the NF-kB-dependent pathway.(4) Calpain is a calcium-activated protease. We found four calpain isoforms and calpain inhibitor calpastatin localized in distinct cell-types of the gastric mucosa. Calpastatin significantly blocks cell migratory capacity.Although we could not show the appearance of strong adherent property of gastric membranes to H. pylori by the decline of glandular structure, we provided substantial understandings to complicated glandular structures which are vulnerable to H. pylori invasion. Less