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

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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.