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

通过不同细胞类型之间的旁分泌机制在胃粘膜细胞中表达高度分化的功能，并且与幽门螺杆菌的粘附特性的出现与其分化功能的下降成反比

• 批准号: 12470118
• 负责人: TAKEUCHI Toshiyuki
• 金额: $ 8.64万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470118/
• 关键词: Gastrin; Gastrin receptor; CCK-B; Furin; TGFβ; Gastric surface mucous (GSM) cells; Chief cells; Calpain; Calpastatin; 萎縮性胃炎; 胃粘膜上皮; 胃壁細胞; 胃主細胞; TGFβRII受容体

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

胃腺至少由11种不同的细胞类型组成，包括胃表面粘液(GSM)细胞(=PIT细胞)、壁细胞、主细胞和肠嗜铬细胞(ECL)。它们的分化受多种生长因子的调节，包括TGFa和TGFb，胃泌素，以及细胞间或细胞间的相互作用信号。通过以下四项研究，我们证明了高度分化的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PIT细胞上。然而，血清胃泌素水平与胃小凹的生长密切相关。原位杂交结果显示，高胃泌素转基因小鼠胃粘膜中CGKB-R基因在中低腺区有微弱分布。因此，胃泌素直接刺激PIT细胞的生长。(2)Furin是一种原蛋白转换酶，分布在上第三层…中更多的是和胃腺的下四分之一区域。我们鉴定了上部的Furin阳性细胞为壁细胞，下部的细胞为主细胞。主细胞表达三种不同形式的TGFb，需要被Furin切割才能激活。TGFa诱导原代培养的主细胞中Furin和TGFb的mRNAs表达增加。(3)TGFa在PIT细胞中高表达。TGFa对GSM细胞具有抗凋亡作用，并能增强Bcl2的表达。这种抗细胞凋亡作用是通过依赖于核因子-kB的途径来实现的。(4)钙蛋白酶是一种钙激活的蛋白水解酶。我们发现在胃粘膜的不同细胞类型中有四种钙蛋白酶亚型和钙蛋白酶抑制剂钙蛋白酶抑制物。虽然我们不能通过腺体结构的下降表现出胃膜对幽门螺杆菌的强烈粘附性，但我们对复杂的腺体结构提供了实质性的理解，这些腺体结构容易受到幽门螺杆菌的侵袭。较少

项目成果

M. Kanai, Y. Konda, Y. Izumi, et al.: "Anti-apoptotic effects of TGF-α on gastric pit cells via NF-κB"Gastoenterology. 121. 56-67 (2001)

M. Kanai、Y. Konda、Y. Izumi 等人：“TGF-α 通过 NF-κB 对胃凹细胞的抗凋亡作用”胃肠病学 121. 56-67 (2001)。

M.Kanai, Y.Konda, Y.Izumi, et al.: "Anti-apoptotic effects of TGF-α on gastric pit cells via NF-κB."Gastroenterology. 121. 56-67 (2001)

M.Kanai、Y.Konda、Y.Izumi 等人：“TGF-α 通过 NF-κB 对胃凹细胞的抗凋亡作用。”胃肠病学。 121. 56-67 (2001)

Nakajima T, Konda Y, Izumi Y, Kanai M, Takeuchi T. et al.: "Gastrin interferes with the differentiation of gastric pit cells and parietal cells"Aliment Pharmacol Ther. 16. 3-9 (2002)

Nakajima T、Konda Y、Izumi Y、Kanai M、Takeuchi T. 等：“胃泌素干扰胃凹细胞和壁细胞的分化”Aliment Pharmacol Ther。

H.Kamimura,H.Yokota,Y.Konda, et al.: "Localization of proprotein-processing endoprotease furin and its substrate TGFβ in rat gastric chief cells"American Journal of Physiology. (in prss). (2001)

H. Kamimura、H. Yokota、Y. Konda 等人：“大鼠胃主细胞中前蛋白加工内切蛋白酶弗林蛋白酶及其底物 TGFβ 的定位”美国生理学杂志（2001 年）。

M.Fujisawa, H.Kamimura, N.Hosaka at al.: "Functional localization of proprotein-convertase furin and its substrate TGFβ receptor-expressing gastric chief cells."Growth Factors. (in press). 1-9 (2004)

M.Fujisawa、H.Kamimura、N.Hosaka 等人：“前蛋白转化酶弗林蛋白酶及其底物 TGFβ 受体表达胃主细胞的功能定位”。生长因子 1-9（出版中）。