Identification of a rare Gli1(+) progenitor cell population contributing to liver regeneration during chronic injury

In adults, hepatocytes are mainly replenished from the existing progenitor pools of hepatocytes and cholangiocytes during chronic liver injury. However, it is unclear whether other cell types in addition to classical hepatocytes and cholangiocytes contribute to hepatocyte regeneration after chronic liver injuries. Here, we identified a new biphenotypic cell population that contributes to hepatocyte regeneration during chronic liver injuries. We found that a cell population expressed Gli1 and EpCAM (EpCAM(+)Gli1(+)), which was further characterized with both epithelial and mesenchymal identities by single-cell RNA sequencing. Genetic lineage tracing using dual recombinases revealed that Gli1(+) nonhepatocyte cell population could generate hepatocytes after chronic liver injury. EpCAM(+)Gli1(+) cells exhibited a greater capacity for organoid formation with functional hepatocytes in vitro and liver regeneration upon transplantation in vivo. Collectively, these findings demonstrate that EpCAM(+)Gli1(+) cells can serve as a new source of liver progenitor cells and contribute to liver repair and regeneration.