Determining the Fate of Hepatic Cells by Lineage Tracing: Facts and Pitfalls

Slow renewal of the epithelial cells by proliferation ensures homeostasis of the liver, but extensive proliferation may occur upon injury. When proliferation is impaired, transdifferentiation of mature cells or differentiation of stem cells allows production of new hepatocytes and cholangiocytes. While lineage tracings using cyclization recombinase (Cre) recombinase-mediated cell labeling represent the gold standard for defining cell fate, there are more variables than was initially realized. This led to controversies about the capacity of liver cells to switch their fate. Here, I review how cells are traced in the liver and highlight the experimental pitfalls that may cause misinterpretations and controversies.