Chronic Liver Injury Induces Conversion of Biliary Epithelial Cells into Hepatocytes

Chronic liver injury can cause cirrhosis and impaired liver regeneration, impairing organ function. Adult livers can regenerate in response to parenchymal insults, and multiple cellular sources have been reported to contribute to this response. In this study, we modeled human chronic liver injuries, in which such responses are blunted, without genetic manipulations, and assessed potential contributions of non-parenchymal cells (NPCs) to hepatocyte regeneration. We show that NPC-derived hepatocytes replenish a large fraction of the liver parenchyma following severe injuries induced by long-term thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment. Through lineage tracing of biliary epithelial cells (BECs), we show that BECs are a source of new hepatocytes and gain an Hnf4α+CK19+ bi-phenotypic state in periportal regions and fibrotic septa. Bi-phenotypic cells were also detected in cirrhotic human livers. Together, these data provide further support for hepatocyte regeneration from BECs without genetic interventions and show their cellular plasticity during severe liver injury. [Display omitted] •Non-parenchymal cells produce hepatocytes in response to severe liver injuries•Biliary epithelial cells (BECs) are a source for hepatocyte regeneration•BECs convert into hepatocytes through an Hnf4α+CK19+ bi-phenotypic state Understanding cellular sources of hepatocyte regeneration is critical for developing effective therapies for chronic liver diseases. Xie and colleagues show that severe liver injuries can, without genetic interventions, induce biliary epithelial cells to significantly contribute to hepatocyte regeneration through direct lineage conversion.