Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish

Abstract

Abstract The liver’s regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.