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Mechanism of sinusoidal endothelial cell proliferation and maturation during hepatic regeneration

肝再生过程中肝窦内皮细胞增殖和成熟的机制

基本信息

批准号：
17591375
负责人：
SHIMIZU Hiroaki
金额：
$ 2.18万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591375/
关键词：
liver regeneration sinusoidal endothelial cell Ito cell hepatectomy

项目摘要

AIMS : The regulatory mechanisms of sinusoidal regeneration after partial hepatectomy remain poorly understood.METHODS : We investigated the expression of angiopoietin (Ang)-1, Ang- 2, Tie-2, and vascular endothelial growth factor (VEGF) in both regenerating liver tissue and isolated liver cells after 70% hepatectomy in rats. Proliferation and apoptosis of sinusoidal endothelial cells (SECs) were also evaluated with proliferating cell nuclear antigen (PCNA) and TUNEL staining, respectively.Results : VEGF mRNA expression was increased with a peak at 72 h after hepatectomy, decreasing thereafter. The expression of Ang-1 mRNA was present at detectable levels before hepatectomy and was increased slowly with a peak at 96 h. Meanwhile, Ang-2 mRNA was hardly detected before hepatectomy, but was remarkably induced at 120 h and 144 h. In isolated cells, VEGF mRNA expression was found mainly in the hepatocyte fraction. Meanwhile, mRNA for Ang-1 and Ang-2 was found in the SEC and hepatic stellate cell (HSC) fractions, but was more prominent in the latter. The PCNA labeling index of SECs increased slowly, reaching a peak at 72 h, whereas apoptotic SECs were detected between 120 h and 144 h.Conclusions : VEGF secreted by hepatocytes may play a key role in SEC proliferation, followed by increased Ang-1, presumably promoting sinusoidal maturation. Thereafter, Ang-2 mainly released from HSCs in the absence of VEGF may contribute to apoptosis of superfluous SECs for cessation of the regenerative process. Ang-Tie system, together with VEGF, plays a critical role in regulating balance between SEC proliferation and apoptosis during sinusoidal regeneration after hepatectomy.

目的：探讨肝部分切除后肝窦再生的调控机制。方法：观察血管生成素(Ang)-1、Ang-2、Tie-2和血管内皮生长因子(VEGF)在大鼠肝部分切除后再生肝组织和肝细胞中的表达。结果：肝切除后肝窦内皮细胞(SECs)中血管内皮生长因子(VEGFm RNA)表达增加，72h达高峰，以后逐渐下降。Ang-1mRNA在肝切除前有表达，96h达高峰，而Ang-2mRNA在肝切除前几乎检测不到，在120h和144h明显诱导表达，在分离的细胞中，血管内皮生长因子主要在肝细胞中表达。同时，Ang-1和Ang-2在SEC和肝星状细胞(HSC)组分中均有表达，但在HSC组分中更为明显。SECs的增殖细胞核抗原标记指数在72h达到高峰，而在120h~144h检测到凋亡的SECs。结论：肝细胞分泌的血管内皮生长因子可能在SEC的增殖中起关键作用，其次是Ang-1的增加，可能促进肝窦的成熟。此后，在缺乏血管内皮生长因子的情况下，主要从HSC释放的Ang-2可能有助于多余的SEC的凋亡，从而停止再生过程。Ang-Tie系统与血管内皮生长因子一起，在肝切除后肝窦再生过程中调节SEC增殖与细胞凋亡之间的平衡起着关键作用。