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

Publication ,  Journal Article
Omenetti, A; Porrello, A; Jung, Y; Yang, L; Popov, Y; Choi, SS; Witek, RP; Alpini, G; Venter, J; Vandongen, HM; Syn, W-K; Baroni, GS ...
Published in: J Clin Invest
October 2008

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.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

October 2008

Volume

118

Issue

10

Start / End Page

3331 / 3342

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Mice
  • Mesoderm
  • Male
  • Liver Cirrhosis, Biliary
  • Ligands
  • Immunology
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Omenetti, A., Porrello, A., Jung, Y., Yang, L., Popov, Y., Choi, S. S., … Diehl, A. M. (2008). Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. The Journal of Clinical Investigation, 118(10), 3331–3342. https://doi.org/10.1172/JCI35875
Omenetti, A., A. Porrello, Y. Jung, L. Yang, Y. Popov, S. S. Choi, R. P. Witek, et al. “Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.The Journal of Clinical Investigation 118, no. 10 (October 2008): 3331–42. https://doi.org/10.1172/JCI35875.
Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. The Journal of clinical investigation. 2008 Oct;118(10):3331–42.
Omenetti, A., et al. “Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.The Journal of Clinical Investigation, vol. 118, no. 10, Oct. 2008, pp. 3331–42. Manual, doi:10.1172/JCI35875.
Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, Diehl AM. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. The Journal of clinical investigation. 2008 Oct;118(10):3331–3342.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

October 2008

Volume

118

Issue

10

Start / End Page

3331 / 3342

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Mice
  • Mesoderm
  • Male
  • Liver Cirrhosis, Biliary
  • Ligands
  • Immunology
  • Humans