Aberrant differentiation and proliferation of the liver epithelial system in chronic liver diseases and liver cancers

Abstract

Despite striking morphological and functional differences, hepatocytes and bile duct cells, composing the liver epithelial system, are derived from albumin-expressing hepatoblasts during development. To understand the pathogenesis of ductular reaction in chronic liver diseases, as well as of liver tumors, it is important to elucidate how these epithelial cells behave in disease states. Mature hepatocytes retain phenotypic plasticity to transdifferentiate into bile duct cells, which is triggered by microenvironmental changes, especially increases in collagenous matrix. Hepatocyte lineage tracing experiments in mice have revealed that ductular reaction in chronic liver diseases could be attributed to both transdifferentiation of hepatocytes at the injured area and robust remodeling of the exisiting bile duct system. Furthermore, an AAV8-mediated efficient hepatocyte lineage tracing system has unexpectedly provided evidence showing that regenerative nodules in cirrhosis may be formed by clonally proliferated hepatocytes, suggesting that hepatocytes may be heterogeneous in regard to the regenerating capacity in response to stimulation instigated by chronic injury. Transformation of hepatocytes in regenerative nodules is associated with dedifferentiation, which is characterized by reactivation of expression of the genes that are actively transcribed in fetal and neonatal livers. Using a mouse hepatocarcinogenesis model induced by hepatocyte-specific somatic integration of various oncogenes, primary liver cancers of hepatocytic origin have been shown to demonstrate widely varying degrees of phenotypic complexity, according to altered differentiation states of transformed hepatocytes via transdifferentiation and dedifferentiation.