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.
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.
Authors: Laurie D DeLeve; Xiangdong Wang; Liping Hu; Margaret K McCuskey; Robert S McCuskey Journal: Am J Physiol Gastrointest Liver Physiol Date: 2004-06-10 Impact factor: 4.052
Authors: Steven A Vokes; Tatiana A Yatskievych; Ronald L Heimark; Jill McMahon; Andrew P McMahon; Parker B Antin; Paul A Krieg Journal: Development Date: 2004-08-04 Impact factor: 6.868
Authors: W Jy; L L Horstman; J J Jimenez; Y S Ahn; E Biró; R Nieuwland; A Sturk; F Dignat-George; F Sabatier; L Camoin-Jau; J Sampol; B Hugel; F Zobairi; J M Freyssinet; S Nomura; A S Shet; N S Key; R P Hebbel Journal: J Thromb Haemost Date: 2004-10 Impact factor: 5.824
Authors: Giuseppe Straface; Tamar Aprahamian; Andrea Flex; Eleonora Gaetani; Federico Biscetti; Roy C Smith; Giovanni Pecorini; Enrico Pola; Flavia Angelini; Egidio Stigliano; John J Castellot; Douglas W Losordo; Roberto Pola Journal: J Cell Mol Med Date: 2008-07-26 Impact factor: 5.310
Authors: Anatoliy I Masyuk; Bing Q Huang; Christopher J Ward; Sergio A Gradilone; Jesus M Banales; Tatyana V Masyuk; Brynn Radtke; Patrick L Splinter; Nicholas F LaRusso Journal: Am J Physiol Gastrointest Liver Physiol Date: 2010-07-15 Impact factor: 4.052
Authors: James H Tabibian; Anatoliy I Masyuk; Tetyana V Masyuk; Steven P O'Hara; Nicholas F LaRusso Journal: Compr Physiol Date: 2013-01 Impact factor: 9.090
Authors: Takashi Tomiyama; Guo-Xiang Yang; Ming Zhao; Weici Zhang; Hajime Tanaka; Jing Wang; Patrick Sc Leung; Kazuichi Okazaki; Xiao-Song He; Qianjin Lu; Ross L Coppel; Christopher L Bowlus; M Eric Gershwin Journal: Cell Mol Immunol Date: 2015-09-21 Impact factor: 11.530
Authors: Petra Hirsova; Samar H Ibrahim; Vikas K Verma; Leslie A Morton; Vijay H Shah; Nicholas F LaRusso; Gregory J Gores; Harmeet Malhi Journal: Hepatology Date: 2016-10-20 Impact factor: 17.425