Abstract
Upon severe and/or chronic liver injury, ectopic emergence and expansion of atypical biliary epithelial-like cells in the liver parenchyma, known as the ductular reaction, is typically induced and implicated in organ regeneration. Although this phenomenon has long been postulated to represent activation of facultative liver stem/progenitor cells that give rise to new hepatocytes, recent lineage-tracing analyses have challenged this notion, thereby leaving the pro-regenerative role of the ductular reaction enigmatic. Here, we show that the expanded and remodelled intrahepatic biliary epithelia in the ductular reaction constituted functional and complementary bile-excreting conduit systems in injured parenchyma where hepatocyte bile canalicular networks were lost. The canalicular collapse was an incipient defect commonly associated with hepatocyte injury irrespective of cholestatic statuses, and could sufficiently provoke the ductular reaction when artificially induced. We propose a unifying model for the induction of the ductular reaction, where compensatory biliary epithelial tissue remodeling ensures bile-excreting network homeostasis.
Highlights
Upon severe and/or chronic liver injury, ectopic emergence and expansion of atypical biliary epithelial-like cells in the liver parenchyma, known as the ductular reaction, is typically induced and implicated in organ regeneration
The ductular reaction has long been postulated to represent the activation of facultative liver stem/progenitor cells that reside in the biliary compartment and give rise to new hepatocytes[11,12], so that the relationship between the ductular reaction and liver regeneration has been intensively studied with primary focus on cell lineages or cell supply[13,14]
Our imaging analyses reveal that the collapse of the bile canalicular network in the liver parenchyma is induced at the early phase of liver pathology in both cholestatic and noncholestatic liver injury conditions, and that the areas for the bile canalicular collapse and the biliary epithelial tissue expansion are statistically correlated
Summary
Upon severe and/or chronic liver injury, ectopic emergence and expansion of atypical biliary epithelial-like cells in the liver parenchyma, known as the ductular reaction, is typically induced and implicated in organ regeneration. Our imaging analyses reveal that the collapse of the bile canalicular network in the liver parenchyma is induced at the early phase of liver pathology in both cholestatic and noncholestatic liver injury conditions, and that the areas for the bile canalicular collapse and the biliary epithelial tissue expansion are statistically correlated Based on these observations, we propose a unifying model for the role of the ductular reaction: it represents an adaptive and compensatory biliary epithelial tissue remodeling process to reconstruct functional bile-excreting network in place of the lost bile canaliculi in the injured liver. CRISPR/ Cas9-based in vivo gene knockout experiment demonstrates that the loss of bile canalicular network induces biliary epithelial tissue expansion and remodeling, lending further support to our proposed model for the ductular reaction
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