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

Publication ,  Journal Article
Omenetti, A; Yang, L; Li, Y-X; McCall, SJ; Jung, Y; Sicklick, JK; Huang, J; Choi, S; Suzuki, A; Diehl, AM
Published in: Lab Invest
May 2007

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.

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Published In

Lab Invest

DOI

ISSN

0023-6837

Publication Date

May 2007

Volume

87

Issue

5

Start / End Page

499 / 514

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Signal Transduction
  • Receptors, Cell Surface
  • Pathology
  • Patched-1 Receptor
  • Patched Receptors
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Mesoderm
 

Citation

APA
Chicago
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Omenetti, A., Yang, L., Li, Y.-X., McCall, S. J., Jung, Y., Sicklick, J. K., … Diehl, A. M. (2007). Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest, 87(5), 499–514. https://doi.org/10.1038/labinvest.3700537
Omenetti, Alessia, Liu Yang, Yin-Xiong Li, Shannon J. McCall, Youngmi Jung, Jason K. Sicklick, Jiawen Huang, Steve Choi, Ayako Suzuki, and Anna Mae Diehl. “Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation.Lab Invest 87, no. 5 (May 2007): 499–514. https://doi.org/10.1038/labinvest.3700537.
Omenetti A, Yang L, Li Y-X, McCall SJ, Jung Y, Sicklick JK, et al. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest. 2007 May;87(5):499–514.
Omenetti, Alessia, et al. “Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation.Lab Invest, vol. 87, no. 5, May 2007, pp. 499–514. Pubmed, doi:10.1038/labinvest.3700537.
Omenetti A, Yang L, Li Y-X, McCall SJ, Jung Y, Sicklick JK, Huang J, Choi S, Suzuki A, Diehl AM. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest. 2007 May;87(5):499–514.

Published In

Lab Invest

DOI

ISSN

0023-6837

Publication Date

May 2007

Volume

87

Issue

5

Start / End Page

499 / 514

Location

United States

Related Subject Headings

  • Zinc Finger Protein Gli2
  • Signal Transduction
  • Receptors, Cell Surface
  • Pathology
  • Patched-1 Receptor
  • Patched Receptors
  • Mice, Mutant Strains
  • Mice, Inbred C57BL
  • Mice
  • Mesoderm