Phenotypic Plasticity of Hepatocytes and Cholangiocytes in Chronic Liver Disease

The hepatic epithelial system, composed of hepatocytes and bile duct cells, exhibits remarkable phenotypic plasticity despite its highly differentiated state. During acute liver injury, hepatocytes rapidly regenerate through self-duplication; however, chronic or repetitive injury induces incomplete regeneration, fibrotic remodeling, and ductular reactions. Historically, a liver progenitor cell (LPC) population was proposed to mediate regeneration when hepatocyte proliferation is impaired, but recent lineage-tracing and single-cell analyses indicate that LPCs contribute minimally, and that most new hepatocytes arise from pre-existing hepatocytes. Ductular reactions, frequently observed in chronic liver diseases, primarily result from proliferation and remodeling of existing bile ducts, with a subset derived from hepatocyte transdifferentiation. Such hepatocyte-to-ductular transitions may help re-establish bile canalicular continuity in damaged tissue. Oncogenic activation in hepatocytes further reveals their plastic potential, producing diverse tumor phenotypes—ranging from hepatocellular carcinoma to cholangiocarcinoma and hepatoblastoma—through transdifferentiation or dedifferentiation programs reminiscent of liver development. These findings suggest that liver regeneration and carcinogenesis share common mechanisms of epithelial reprogramming. Future research should aim to identify subsets of hepatocytes capable of sustained replication and to elucidate how the injured microenvironment governs epithelial cell fate through processes such as paligenosis. Understanding and modulating hepatic epithelial plasticity may provide new strategies for treating chronic liver diseases and liver cancer.

Keywords: Cholangiocytes, dedifferentiation, ductular reaction, hepatocytes, liver progenitor cells, phenotypic plasticity, primary liver cancers, transdifferentiation