Cholangiocytes act as Facultative Liver Stem Cells during Impaired Hepatocyte Regeneration

Alexander Raven, Wei-Yu Lu, Tak Yung Man, Sofia Ferreira-Gonzalez, Eoghan O'Duibhir, Benjamin J Dwyer, John P Thomson, Richard R. Meehan, Roman Bogorad, Victor Koteliansky, Yuri Kotelevtsev, Charles Ffrench-Constant, Luke Boulter, Stuart J. Forbes

Research output: Contribution to journalArticlepeer-review

Abstract

After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired—a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, 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.
Original languageEnglish
Pages (from-to)350–354
Number of pages5
JournalNature
Volume547
Issue number7663
Early online date12 Jul 2017
DOIs
Publication statusPublished - 20 Jul 2017

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