Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
Alessia Omenetti, … , Detlef Schuppan, Anna Mae Diehl
Alessia Omenetti, … , Detlef Schuppan, Anna Mae Diehl
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3331-3342. https://doi.org/10.1172/JCI35875.
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Research Article

Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans

Abstract

Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis.

Authors

Alessia Omenetti, Alessandro Porrello, Youngmi Jung, Liu Yang, Yury Popov, Steve S. Choi, Rafal P. Witek, Gianfranco Alpini, Juliet Venter, Hendrika M. Vandongen, Wing-Kin Syn, Gianluca Svegliati Baroni, Antonio Benedetti, Detlef Schuppan, Anna Mae Diehl

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Figure 5

Soluble factors released by myofibroblasts change the gene expression profile of cocultured cholangiocytes.

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Soluble factors released by myofibroblasts change the gene expression pr...
(A and B) GO analysis of microarray data from cholangiocytes cocultured with MF-HSCs, compared with cholangiocyte monocultures. Each gene probe having an expression ratio above 1.500 and below 0.666 was then assigned to its corresponding GO families. GO sets were therefore ranked based on the total number of genes belonging to them. GO families associated with more than 10% of selected genes were discarded, in order to increase the specificity of the GO analysis. This subpopulation of GO sets was further split into 2 groups, one accounting for at least 60% of this subpopulation, and the other one accounting for the remaining percentage (<40%). A pie chart was then generated using individual names for the first group of GO families, while GO sets belonging to the second group were collectively designated as “other.” (A) Upregulated GO gene sets. (B) Downregulated GO gene sets. Numbers in parenthesis represent altered genes belonging to that specific family. Original pie charts and legends are provided as Supplemental Figures 1 and 2. Complete lists of GO families and EASE scores are reported in Tables 1 and 2 and Supplemental Table 2.