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Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.

Publication ,  Journal Article
Witek, RP; Yang, L; Liu, R; Jung, Y; Omenetti, A; Syn, W-K; Choi, SS; Cheong, Y; Fearing, CM; Agboola, KM; Chen, W; Diehl, AM
Published in: Gastroenterology
January 2009

BACKGROUND & AIMS: Angiogenesis contributes to vascular remodeling during cirrhosis. In cirrhotic livers, cholangiocytes, and myofibroblastic hepatic stellate cells (MF-HSC) produce Hedgehog (Hh) ligands. During embryogenesis Hh ligands are released from ligand-producing cells in microparticles and activate Hh signaling in endothelial cells. We studied whether adult liver cell-derived microparticles contain Hh ligands that alter hepatic sinusoidal endothelial cells (SEC). METHODS: MF-HSC and cholangiocytes were exposed to platelet-derived growth factor to induce Hh ligands; microparticles were isolated from medium, analyzed by transmission electron microscopy and immunoblots, and applied to Hh-reporter-containing cells. Microparticles were obtained from serum and bile of rats after bile duct ligation (BDL) or sham surgery and applied to normal primary liver SEC with or without cyclopamine, an Hh signaling inhibitor. Effects on SEC gene expression were evaluated by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Hh target gene expression and SEC activation markers were compared in primary SEC and in liver sections from healthy and BDL rats. RESULTS: Platelet-derived growth factor-treated MF-HSC and cholangiocytes released exosome-enriched microparticles containing biologically-active Hh ligands. BDL increased release of Hh-containing exosome-enriched microparticles into plasma and bile. Transmission electron microscopy and immunoblots revealed similarities among microparticles from all sources; all microparticles induced similar Hh-dependent changes in SEC gene expression. SEC from healthy livers did not express Hh target genes or activation markers, but both were up-regulated in SEC after BDL. CONCLUSIONS: Hh-containing exosome-enriched microparticles released from liver cells alter hepatic SEC gene expression, suggesting a novel mechanism for cirrhotic vasculopathy.

Duke Scholars

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

January 2009

Volume

136

Issue

1

Start / End Page

320 / 330.e2

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-sis
  • Platelet-Derived Growth Factor
  • Male
  • Liver Cirrhosis
  • Ligation
  • Hypertension, Portal
  • Hepatocytes
 

Citation

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Witek, R. P., Yang, L., Liu, R., Jung, Y., Omenetti, A., Syn, W. K., … Diehl, A. M. (2009). Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology, 136(1), 320.e2-330.e2.
Witek, R. P., L. Yang, R. Liu, Y. Jung, A. Omenetti, W. K. Syn, S. S. Choi, et al. “Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.Gastroenterology 136, no. 1 (January 2009): 320.e2-330.e2.
Witek RP, Yang L, Liu R, Jung Y, Omenetti A, Syn WK, et al. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology. 2009 Jan;136(1):320.e2-330.e2.
Witek, R. P., et al. “Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.Gastroenterology, vol. 136, no. 1, Jan. 2009, pp. 320.e2-330.e2.
Witek RP, Yang L, Liu R, Jung Y, Omenetti A, Syn WK, Choi SS, Cheong Y, Fearing CM, Agboola KM, Chen W, Diehl AM. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology. 2009 Jan;136(1):320.e2-330.e2.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

January 2009

Volume

136

Issue

1

Start / End Page

320 / 330.e2

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-sis
  • Platelet-Derived Growth Factor
  • Male
  • Liver Cirrhosis
  • Ligation
  • Hypertension, Portal
  • Hepatocytes