Cholangiocytes act as Facultative Liver Stem Cells during Impaired Hepatocyte Regeneration

Following liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired, a feature of human chronic liver disease1,2. It is contested whether other liver cell types can regenerate hepatocytes3–5. Here, we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. Firstly, loss of β1-Integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, and ~25% of hepatocytes being derived from a non-hepatocyte origin. Secondly cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-Integrin knockdown or p21 over-expression, resulting in the significant emergence of cholangiocyte derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.