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A Role of Protein Tyrosine Phosphorylation in Bile Ductular Metaplasia of Hepatocytes

蛋白酪氨酸磷酸化在肝细胞胆管化生中的作用

基本信息

批准号：
11670203
负责人：
NISHIKAWA Yuji
金额：
$ 2.05万
依托单位：
Akita University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670203/
关键词：
Bile ductular reaction (metaplasia)Hepatocytes Bile duct cells Liver fibrosis Chronic liver disease Three-dimensional culture Liver non-parenchymal cells Kupffer cells 蛋白質チロシンリン酸化バナジウム酸肝硬変培養

项目摘要

Bile ductules are known to increase in the portal area in chronic liver diseases with portal fibrosis and inflammation (ductular reaction). It has been considered that newly formed bile ductules may be derived from periportal hepatocytes, although the mechanism is not clear. In this study, we investigated a possible role of protein tyrosine phosphorylation in the bile ductular metaplasia of hepatocytes using a three dimensional culture system. We also studied whether liver non-parenchymal cells, especially Kupffer cells, affected hepatocyte differentiation. Summary of our results are as follows.(1) When sheroidal aggregates of mature rat hepatocytes were embedded within a three-dimensional collagen gel matrix, dendritic cellular processes elongated from the aggregates and these processes expressed bile duct-specific cytokeratins, such as cytokeratins 19 and 20. These cellular processes formed bile duct-like tubular structures with distinct basal membrane after 3 weeks in vitro.(2) A prototype protein tyrosine phosphatase inhibitor, sodium orthovanadate, which increased protein tyrosine phosphorylation levels of cellular proteins, promoted the dendritic morphogenesis and expression of the bile duct-specific cytokeratins of cultured hepatocytes.(3) The dendritic morphogenesis of cultured hepatocytes was markedly enhanced by soluble factors derived from liver non-parenchymal cells, especially interleukin 6 and transforming growth factor α, which are known to be secreted by Kupffer cells.Our data suggested that bile ductular differentiation of mature hepatocytes within the collagenous matrix might be regulated by protein tyrosine phosphorylation and affected by non-parenchymal cell-derived soluble factors.

已知在伴有门静脉纤维化和炎症（胆管反应）的慢性肝病中，门静脉区域的胆管会增加。人们认为新形成的胆管可能源自汇管周围肝细胞，但其机制尚不清楚。在这项研究中，我们使用三维培养系统研究了蛋白质酪氨酸磷酸化在肝细胞胆管化生中的可能作用。我们还研究了肝脏非实质细胞，尤其是库普弗细胞是否影响肝细胞分化。我们的结果总结如下。（1）当成熟大鼠肝细胞的鞘状聚集体嵌入三维胶原凝胶基质中时，树突状细胞突起从聚集体中伸长，并且这些突起表达胆管特异性细胞角蛋白，例如细胞角蛋白19和20。这些细胞突起形成胆管样管状结构体外3周后基底膜清晰。(2)原型蛋白酪氨酸磷酸酶抑制剂原钒酸钠，可增加细胞蛋白的蛋白酪氨酸磷酸化水平，促进培养肝细胞的树突形态发生和胆管特异性细胞角蛋白的表达。(3)培养肝细胞的树突形态发生来自肝脏非实质细胞的可溶性因子，特别是白细胞介素 6 和转化生长因子 α，已知由库普弗细胞分泌，肝细胞显着增强。我们的数据表明，胶原基质内成熟肝细胞的胆管分化可能受蛋白质酪氨酸磷酸化的调节，并受非实质细胞来源的影响可溶性因素。