The liver is unmatched in regenerative capacity. However, when exhausted, the liver is predisposed to various diseases based on injury types and causal agents. Although hepatocytes have been proposed to be the main source of new hepatocytes during regeneration, the existence of specialized liver stem cells has been long debated. In mice, oval cells or ductal cells have been postulated as such stem/progenitor pool. Exhaustive works from different laboratories have shown that in genetically unmodified mice, oval cells, or by extension ductal cells, only contribute marginally in producing new hepatocytes during liver regeneration, thus indicating that hepatocytes are the main regenerative cell source. In this debated context, we identified a new population of periportal hepatocytes in the normal mouse liver. These cells we termed hybrid hepatocytes (HybHP) express low levels of the transcription factor Sox9. Using complementary lineage tracing tools, we demonstrated that HybHP regenerate the liver after chronic hepatocyte depleting injuries. Here, we describe the two-step genetic recombination method that allowed us to study HybHP’s lineage in two established models of liver injury.

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