Impairing hepatocyte regeneration to determine the regenerative capacity of the biliary epithelium
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Date
30/06/2018Author
Raven, Alexander Philip
Metadata
Abstract
Liver injury stimulates hepatocyte proliferation, regenerating the liver through self-replication.
In cases where there is severe, repetitive, parenchymal damage, as seen in
human chronic liver disease, hepatocyte mediated regeneration becomes impaired. In
this setting it is currently unclear whether endogenous biliary epithelial cells can
repopulate the hepatocyte compartment. This thesis therefore aimed to address this
point by lineage tracing the main two liver epithelia populations on a background of
impaired hepatocyte regeneration.
To impair regeneration, an Itgb1 transgene was specifically deleted, conditionally,
from the hepatocyte epithelium. Long-term loss of β1-Integrin alone or with additional
injury caused an epithelial ductular reaction of biliary origin. Alongside β1-Integrin
ablation, the hepatocyte epithelium was also labelled with a heritable
ROSA26LSLtdTomato reporter. Impaired hepatocyte regeneration mediated by β1-
integrin ablation resulted in 25% of hepatocytes becoming tdTomato negative (non-hepatocyte
derived). To verify that the non-hepatocyte mediated regeneration was
originating from the biliary epithelium, anti-Itgb1 RNAi was administrated to
K19CreERT LSLtdTomato mice. Resulting in tdTomato positive hepatocytes that had
differentiated from the labelled tdTomato positive biliary epithelial cells.
In summary, this thesis demonstrates that hepatocyte β1-Integrin ablation combined
with toxic damage causes marked ductular reactions and results in a substantial
regeneration of functional hepatocytes from the biliary epithelium.