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Mechanism of hepatocyte proliferation through vascular mediators secreted by sinusoidal endothelial cells

肝窦内皮细胞分泌的血管介质促进肝细胞增殖的机制

基本信息

批准号：
04670411
负责人：
HASHIMOTO Naoaki
金额：
$ 1.34万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

Vascular endothelial cells secretes various chemical mediators, and thus they control the function of various cells around them. Liver is characterized by a unique structure named sinusoids, where hepatocytes and sinusoidal endothelial cells face directly across Disse spaces. We thought that this structure was suitable for liver regeneration ; unique physiological function of the liver. We hypothesized that sinusoidal endothelial cells would regulate the proliferation of hepatocytes through secretion of vascular mediators.We first established the primary culture system for rat sinusoidal endothelial cells, and compared them with bovine carotide endothelial cells, widely used cell priparation for experimental research of this field. Both cells secreted endothelin, typical vascular mediator, although there was difference in secreted amount. Main prostanoid they secreted were PGE2 and PGI2, respectively. PGE2 secretion of sinusoidal endothelial cells was regulated by extracellular ATP through purinergic receptors. The profile of prostanoid secreted by sinusoidal endothelial cells was diffrent from that by Kupffer cells. PGE2 was the main prostanoid that stimulated DNA systhesis of cultured hepatocytes in the presence of insulin and EGF.It acted through PGE2 receptor, which was coupled with inhibitory G protein suppressed by pertussis toxin. This suggested that the receptor was EP3 subtype, which was confirmed by examining the expression of mRNA on this subtype with mutagenic RT-PCR method.These findings seems to support our hypothesis, and were pulished in literature as listed in the other page.

血管内皮细胞分泌各种化学介质，因此它们控制周围各种细胞的功能。肝脏的特征在于称为窦状隙的独特结构，其中肝细胞和窦状隙内皮细胞直接面对Disse空间。我们认为这种结构适合于肝脏再生，具有独特的肝脏生理功能。我们假设肝窦内皮细胞通过分泌血管介质来调节肝细胞的增殖，首先建立了大鼠肝窦内皮细胞的原代培养体系，并与牛胡萝卜素内皮细胞进行了比较，广泛应用于该领域的实验研究。两种细胞均分泌内皮素，内皮素是典型的血管介质，但分泌量不同。它们分泌的前列腺素主要为PGE_2和PGI_2。细胞外ATP通过嘌呤受体调节窦状隙内皮细胞PGE 2的分泌。肝窦内皮细胞分泌前列腺素的模式与枯否细胞不同。PGE_2是胰岛素和EGF刺激肝细胞DNA合成的主要前列腺素，它通过PGE_2受体与百日咳毒素抑制的抑制性G蛋白偶联发挥作用。用RT-PCR方法检测该受体的mRNA表达，证实该受体为EP 3亚型，这些结果支持了我们的假设，并已在文献中发表，见另页。