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Mechanism of Liver Organogenesis and Its Application to Liver

肝脏器官发生机制及其在肝脏中的应用

基本信息

批准号：
14370376
负责人：
MIYAZAKI Masaru
金额：
$ 9.02万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

To clarify the mechanism of sinusoidal endothelial cell(SEC) proliferation after hepatectomy, the expression of vascular endothelial growth factor(VEGF) and VEGF-receptor of the regenerating liver were evaluated with 70% hepatectomy model in the rats. The expression of VEGF mRNA was increased markedly between 48 and 72 hr after hepatectomy. The immunohistochemical staining revealed that expression of VEGF started to increase 24 hr after hepatectomy, with a peak at 72 hr. Expression of flt-1 and KDR/flk-1 was observed along the sinusoids even before hepatectomy, but was increased between 72 and 120 hr. Furtheremore, VEGF production by cultured hepatocytes isolated 72 hr after hepatectomy was siginificantly increased. The PCNA labeling index of the SECs exhibited a delayed and slower regenerative response in comparison to the hepatocytes, teaching a peak at 72 hr. These data strongly suggest that VEGF secreted by proliferating hepatocytes may represent an important stimulator of SEC proliferation.Furthermore, we focused on the research of Angiopoietin-Tie system that has been shown to regulate liver organogenesis through the modulation of VEGF. Early endothelial cells in mouse embryo surround newly specified hepatic endoderm and delimit the mesenchymal domain into which the liver bud grows. In flk-1 mutant embryo, which lack endothelial cells, hepatic specification occurs, but liver morphogenesis fails prior to mesenchyme invasion. It is concluded that vasculogenic endothelial cells and nascent vessels are critical for the earliest stages of organogenesis, prior to blood vessel function.

为探讨肝切除术后肝窦内皮细胞（SEC）增殖的机制，采用大鼠70%肝切除模型，观察再生肝中血管内皮生长因子（VEGF）及其受体的表达。肝切除后48 ~ 72小时VEGF mRNA表达明显增加。免疫组织化学染色显示，VEGF表达在肝切除后24 h开始增加，72 h达高峰，flt-1和KDR/flk-1在肝切除前沿着肝窦表达，但在72 ~ 120 h表达增加，而且，肝切除后72 h分离的培养肝细胞VEGF的表达显著增加。与肝细胞相比，SEC的PCNA标记指数显示出延迟和较慢的再生反应，在72 h时达到峰值。这些数据强烈地表明，由增殖的肝细胞分泌的VEGF可能代表SEC增殖的重要刺激物。此外，我们集中于已被证明通过调节VEGF来调节肝脏器官发生的血管生成素-Tie系统的研究。小鼠胚胎早期的内皮细胞围绕着新分化的肝内胚层，并界定了肝芽生长的间充质区域。在flk-1突变胚胎，缺乏内皮细胞，肝特化发生，但肝形态发生失败前间充质入侵。它的结论是血管生成内皮细胞和新生血管的器官形成的最早阶段，血管功能之前是至关重要的。