Identification of hepatocyte-primed biliary epithelial cells in the homeostatic liver by in vivo lentiviral gene transfer to mice and non-human primates [scRNA-Seq]
Liver regeneration is supported by hepatocytes and, in certain conditions, biliary epithelial cells (BEC). BEC are facultative liver stem cells, able to form organoids in culture and engraft in damaged livers. However, BEC heterogeneity in the homeostatic liver remains to be fully elucidated. Here, we exploited in vivo systemic lentiviral vector (LV) administration to achieve efficient and life-long gene transfer to BEC in mice. We found that LV-marked BEC retain organoid-formation potential and predominantly respond to liver damage, however, are less clonogenic and display more hepatocyte-primed transcriptome compared to untransduced BEC. We thus identify a BEC subset committed to hepatocyte lineage in the absence of liver damage, characterized by a transcriptional network orchestrated by hepatocyte nuclear factor 4a. We also report in vivo targeting of such BEC in non-human primates. This work highlights intrinsic BEC heterogeneity and that in vivo LV gene transfer to the liver may persist following BEC-mediated repair of hepatic damage. Overall design: Single-cell experiment of two samples of biliary epithelial cells (BEC) from non-human primates (NHP) livers enriched in cholangiocytes.