Journal
NATURE
Volume 547, Issue 7663, Pages 350-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature23015
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Funding
- UK Medical Research Council (MRC) [MC_PC_U127574433]
- MRC [MR/L012766/1, MR/K017047/1]
- UK Regenerative Medicine Platform [MR/K026666/1]
- MRC [MR/L012766/1, MC_PC_U127574433, MR/K017047/1, MR/K026666/1] Funding Source: UKRI
- Medical Research Council [1356047, MR/L012766/1, MR/K017047/1, MR/K026666/1, G0700711B, 1802904, MC_PC_U127574433] Funding Source: researchfish
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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(1,2). It is unclear whether other liver cell types can regenerate hepatocytes(3-5). 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 beta 1-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 beta 1-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.
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