Adult HNF1beta+ cells give rise to oval cells but do not significantly contribute to normal homeostasis or injury repair of hepatocytes in mice

In response to liver injury or loss of liver mass, hepatocytes and cholangiocytes proliferate to replace the injured tissue. However, in case of chronic liver and biliary disease, when hepatocyte and cholangiocyte proliferation is impaired, an expansion of small putative progenitors is observed (oval cell response). Oval cells reside in a niche close to the terminal bile ducts, called canals of Hering, and are believed to give rise to both, hepatocytes and bile ducts. Though controversially debated, these progenitors were recently reported to not only give rise to hepatocytes after liver injury but even provide a continuous supply of hepatocytes of the entire liver in normal homeostasis (“streaming hypothesis”).

Here, we identified quiescent oval cells to express the biliary marker HNF1β. We therefore established a genetic mouse model that allows efficient expression of a fluorescent protein (tdTomato) in HNF1β+ cells upon Tamoxifen injection in order to define the cellular destiny and plasticity of this putative adult hepatic progenitor compartment. After applying various liver injury models almost all oval cells expressed tdTomato, indicating that they were the progeny of the adult HNF1β+ compartment. However, we failed to detect significant hepatocyte neogenesis from tdTomato labelled progenitors both in normal homeostasis and after liver injury.

Conclusion: Adult HNF1β+ cells give rise to oval cells but do not significantly contribute to normal homeostasis or injury repair of hepatocytes in mice. Our results provide further evidence against the “streaming liver hypothesis”.