Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocyt...

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Bibliographic Details
Published in:Laboratory investigation 2007-05, Vol.87 (5), p.499-514
Main Authors: Omenetti, Alessia, Yang, Liu, Li, Yin-Xiong, McCall, Shannon J, Jung, Youngmi, Sicklick, Jason K, Huang, Jiawen, Choi, Steve, Suzuki, Ayako, Diehl, Anna Mae
Format: Article
Language:English
Subjects:
Animals
Bile Ducts - metabolism
Bile Ducts - pathology
Bile Ducts - surgery
biliary fibrosis
Biological and medical sciences
Biomarkers - metabolism
Biotechnology
Cell Survival
Cells, Cultured
cholangiocyte
cholestasis
Disease Models, Animal
Epithelium - metabolism
Fundamental and applied biological sciences. Psychology
Gastroenterology. Liver. Pancreas. Abdomen
hedgehog
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
hepatic stellate cells
Hydroxyproline - metabolism
Investigative techniques, diagnostic techniques (general aspects)
Kruppel-Like Transcription Factors - metabolism
Kupffer Cells - metabolism
Kupffer Cells - pathology
Ligation
Liver - metabolism
Liver - pathology
Liver Cirrhosis, Biliary - etiology
Liver Cirrhosis, Biliary - metabolism
Liver Cirrhosis, Biliary - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mesoderm - metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Other diseases. Semiology
Patched Receptors
Patched-1 Receptor
Receptors, Cell Surface - deficiency
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Signal Transduction
Zinc Finger Protein Gli2
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Summary:In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal–epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.
ISSN:0023-6837
1530-0307
DOI:10.1038/labinvest.3700537