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”.
