Liver regeneration by a population of midzone-located mesenchymal-hepatocyte hybrid cells

Regenerative medicine relies on deep understanding of the mechanisms of organ repair and regeneration. The liver, an organ with critical metabolic functions carried out by hepatocytes located in zones 1-3 of liver lobules, has the capacity to fully regenerate itself, which is mainly attributable to midzone hepatocytes. Yet, how differentiated midzone hepatocytes execute transzone regeneration and quickly recover most of the liver mass remains a myth. Here, we uncover a mesenchymal-hepatocyte population (13.7% of total hepatocytes) that are derived from Twist2-lineage EpCAM+ progenitors, midzone-located, highly polyploidy, and equipped with great mitogenic and migratory capabilities to the detriment of metabolism. They regenerate about 50% of new hepatocytes and repopulate zones 1 and 3 in liver regeneration. Mechanistically, expansion of these cells is negatively controlled by Notch1 signaling. This study has thus uncovered a hepatocyte subpopulation with great proliferation potential and important mechanisms of liver regeneration.