Lineage Tracing Reveals the Bipotency of SOX9+ Hepatocytes during Liver Regeneration

Abstract

Elucidation of the role of different cell lineages in the liver could offer avenues to drive liver regeneration. Previous studies showed that SOX9⁺ hepatocytes can differentiate into ductal cells after liver injuries. It is unclear whether SOX9⁺ hepatocytes are uni- or bipotent progenitors at a single-cell level during liver injury. Here, we developed a genetic tracing system to delineate the lineage potential of SOX9⁺ hepatocytes during liver homeostasis and regeneration. Fate-mapping data showed that these SOX9⁺ hepatocytes respond specifically to different liver injuries, with some contributing to a substantial number of ductal cells. Clonal analysis demonstrated that a single SOX9⁺ hepatocyte gives rise to both hepatocytes and ductal cells after liver injury. This study provides direct evidence that SOX9⁺ hepatocytes can serve as bipotent progenitors after liver injury, producing both hepatocytes and ductal cells for liver repair and regeneration.