Ductular hepatocytes.

Ductular hepatocytes are observed in the livers of both experimental animals and man under various conditions of severe toxin-, carcinogen- or viral-induced hepatic injury with prominent loss of parenchymal hepatocytes. These unique hepatic epithelial cells are characterized by phenotypic traits that are intermediate between those of hepatocytes and intrahepatic biliary epithelium. The origin of ductular hepatocytes is controversial, but it has been hypothesized that they may represent a transitional cell stage associated with either (1) a ductular metaplasia of parenchymal hepatocytes into intrahepatic biliary epithelium, (2) a metaplastic conversion of intrahepatic bile duct or ductular epithelium into hepatocytes, or (3) differentiation of a putative liver stem cell along the hepatocyte lineage. Depending on the liver disease state being investigated, evidence is presented to support all three of these possibilities. Of particular interest is the increasing evidence supporting the existence of a facultative pluripotent stem-like cell associated with the intrahepatic biliary tract, which appears capable of differentiating into various gut endoderm-derived cell types, including hepatocytes, small intestinal mucosal cells, and pancreatic acinar cells. Ductular cells of pancreas have also been demonstrated to alter their differentiation commitment under various induced conditions of pancreatic injury and regeneration, so as to give rise to pancreatic hepatocytes. The presence of a putative stem-like cell in liver together with the plasticity exhibited by some hepatocytes and biliary epithelial cells in various forms of severe hepatic and biliary tract injury can have important implications for carcinogenesis and aberrant regenerative responses in liver. In addition, novel in vivo and cell culture models have been developed, which are serving as potentially powerful tools for investigating the effects of specific growth factors, extracellular matrix components, hormones and other agents on the ability of nonparenchymal epithelial liver cell types to differentiate into hepatocyte-like cells.