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Roles of Hepatoma-derived growth factor(HDGF) on the proliferation and differentiation of hepatic stem cells and liver development

肝细胞生长因子(HDGF)对肝干细胞增殖分化及肝脏发育的作用

基本信息

批准号：
15590699
负责人：
NAKAMURA Hideji
金额：
$ 2.24万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Hepatoma-derived growth factor(HDGF) is a heparin-binding protein, which has been purified the conditioned media of HuH-7 hepatoma cells. Recent studies suggest that HDGF is significantly involved in the development of the liver, cardiovascular system, gut and kidney. In the present study, we investigated the roles of HDGF in the cellular proliferation and differentiation of hepatic progenitor cells, including oval cells, and in the hepatic ontogeny. Hepatic oval cells are one of bipotential hepatic progenitor cells, which can differentiate to both parenchymal hepatocytes and bile duct cells. We analyzed the expression of HDGF in rat liver after acetoaminofluorene/partial hepatectomy treatment by Western blot, Northern blot, immunohistochemisry and in situ hybridization. The expression levels of HDGF by Northern blot and Western blot are parallel to the number of oval cells appeared in the liver. HDGF was expressed in oval cells by in situ hybridization, and more strongly in the nucleu … More s than the cytoplasm by immunohistochemistry. In rat oval cell line, Oct15-5,HDGF was also prominently expressed both in the nucleus and cytoplasm, but in dominantly in the nucleus. Recombinant HDGF mildly stimulated the proliferation of Oct15-5 cells. PPAR-γ ligand, 15d-prostaglandins(PG) J2 inhibited the proliferation of Oct15-5 cells, and significantly suppressed the expression of HDGF. Thus, these data suggest that HDGF plas an important roles on the proliferation of oval cells.We generated HDGF transgenic mouse using albumin promoter. In normal liver, the expression of glucose-6-phoshatase(G-6-Pase) decreases and tryptophan oxygenase(TO) is significantly induced through hepatocyte maturation after birth, however in the liver of HDGF transgenic mouse, the expression of G-6-Pase was not suppressed and TO was not induced at 12 weeks after birth. These findings suggest that the continuous over-expression of HDGF may suppress the differentiation of hepatocytes.Present findings suggest that HDGF should play important roles on the proliferation and differentiation of hepatic progenitor cells in liver ontogeny. Less

肝癌衍生生长因子(HDGF)是一种肝素结合蛋白，已从HH-7肝癌细胞的条件培养液中纯化出来。最近的研究表明，HDGF与肝脏、心血管系统、肠道和肾脏的发育密切相关。在本研究中，我们研究了HDGF在包括卵圆细胞在内的肝祖细胞的细胞增殖和分化中的作用，以及在肝脏个体发育中的作用。肝卵圆细胞是一种具有双潜能的肝祖细胞，可向肝实质细胞和胆管细胞分化。采用Western印迹、Northern印迹、免疫组织化学和原位杂交等方法，分析乙酰氨基荧组大鼠肝部分切除后肝组织中HDGF的表达。Northern印迹和Western印迹显示肝组织中HDGF的表达水平与肝内出现的卵圆细胞数呈平行关系。原位杂交结果显示，hdgf在卵圆细胞中有表达，在细胞核…中表达更强。免疫组织化学显示S阳性细胞多于胞浆。在大鼠卵圆细胞系Oct15-5中，HDGF在胞核和胞浆均有显著表达，但以胞核表达为主。重组HDGF对Oct15-5细胞的增殖有轻度刺激作用。PPAR-γ配体15d-前列腺素(PG)J2抑制OCT15-5细胞的增殖，并显著抑制HDGF的表达。由此可见，HDGF Pla在卵圆细胞的增殖中起着重要的作用。在正常肝脏中，葡萄糖-6-磷酸酶(G-6-Pase)的表达在出生后随着肝细胞的成熟而降低，色氨酸加氧酶(TO)被显著诱导，而在HDGF转基因小鼠的肝脏中，G-6-Pase的表达在出生后12周没有受到抑制，TO也没有被诱导。这些结果提示，HDGF的持续过表达可能抑制肝细胞的分化，提示HDGF在肝脏个体发育中对肝祖细胞的增殖和分化可能起重要作用。较少