Genetic tracing of hepatocytes in liver homeostasis, injury, and regeneration

J Biol Chem. 2017 May 26;292(21):8594-8604. doi: 10.1074/jbc.M117.782029. Epub 2017 Apr 4.


The liver possesses a remarkable capacity to regenerate after damage. There is a heated debate on the origin of new hepatocytes after injuries in adult liver. Hepatic stem/progenitor cells have been proposed to produce functional hepatocytes after injury. Recent studies have argued against this model and suggested that pre-existing hepatocytes, rather than stem cells, contribute new hepatocytes. This hepatocyte-to-hepatocyte model is mainly based on labeling of hepatocytes with Cre-recombinase delivered by the adeno-associated virus. However, the impact of virus infection on cell fate determination, consistency of infection efficiency, and duration of Cre-virus in hepatocytes remain confounding factors that interfere with the data interpretation. Here, we generated a new genetic tool Alb-DreER to label almost all hepatocytes (>99.5%) and track their contribution to different cell lineages in the liver. By "pulse-and-chase" strategy, we found that pre-existing hepatocytes labeled by Alb-DreER contribute to almost all hepatocytes during normal homeostasis and after liver injury. Virtually all hepatocytes in the injured liver are descendants of pre-existing hepatocytes through self-expansion. We concluded that stem cell differentiation is unlikely to be responsible for the generation of a substantial number of new hepatocytes in adult liver. Our study also provides a new mouse tool for more precise in vivo genetic study of hepatocytes in the field.

Keywords: cell differentiation; hepatocyte; lineage trace; liver injury; mouse genetics; progenitor cell; regeneration; replenish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Tracking / methods
  • Hepatocytes* / metabolism
  • Hepatocytes* / pathology
  • Integrases / biosynthesis
  • Integrases / genetics
  • Liver Regeneration*
  • Liver* / injuries
  • Liver* / metabolism
  • Liver* / pathology
  • Mice
  • Mice, Transgenic
  • Stem Cells* / metabolism
  • Stem Cells* / pathology


  • Cre recombinase
  • Integrases