UCSF

Cell plasticity refers to the ability of cells can convert their phenotypic identity, without genetic mutation, in response to environmental stimuli. In the mouse liver, hepatocytes and cholangiocytes have been shown to act as each other’s facultative stem cell in cases of severe liver injury where one cellular compartment is unable to regenerate itself through normal mitosis. Recently, hepatocyte plasticity has also been suggested to play a role in tumorigenesis as mouse hepatocytes have been shown to act as an alternative cell-of-origin for intrahepatic cholangiocarcinomas (ICC). However, whether hepatocyte plasticity is a trait unique to mouse hepatocytes or whether it is a trait shared with human hepatocytes remains to be determined.

In this study, we investigate human hepatocyte plasticity during liver injury and its role in ICC tumorigenesis. We first establish a mouse model of Alagille syndrome lacking all peripheral intrahepatic bile ducts combined with severe immune deficiency. We find that primary human hepatocytes (pHeps) transplanted into these mice transdifferentiate into cholangiocytes with high efficiency and are capable of organizing to form authentic bile ducts that connect to a mouse’s pre-existing hilar bile ducts and drain bile. In humanizing the biliary system of mice, we show that human hepatocyte plasticity can be leveraged to regenerate a missing biliary system, and we create a novel platform to study basic human cholangiocyte biology.

We next investigate the role of human hepatocyte plasticity and its contribution to ICC tumorigenesis. We find that pHeps transduced with oncogenic lentiviruses and transplanted into an immunodeficient mouse model of chronic liver disease can develop into ICCs. We determine that these humanized ICCs phenotypically resemble ICCs from patients and we identify the minimal and necessary oncogenic combination required to induce pHep-to-ICC transformation. We are currently using bulk RNAsequencing to transcriptomically compare our humanized ICCs with patient-derived ICCs to determine their authenticity and to identify which gene perturbations are the crucial drivers for pHep-to-ICC transformation. In generating a humanized mouse model of ICC from pHeps, we have not only proven that human hepatocytes can be the cell-of-origin for ICCs, but we have also opened the doors to studying this disease in a more clinically relevant context.