Abstract
Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin-dependent kinase 2 (Cdk2) and controls cell cycle re-entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)-based approach. CcnE1-siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL/6 wild-type (WT) mice, delivery of stabilized siRNA using a liposome-based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45+ cells after single injection. Acute CCl4 -mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45+ leukocytes. Pretreatment with CcnE1-siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury,...Continue Reading
References
Jun 1, 1995·Journal of Hepatology·K IshakR N MacSween
May 1, 1995·Molecular and Cellular Biology·M OhtsuboM Pagano
Jan 15, 1997·European Journal of Biochemistry·W F De AzevedoS H Kim
Feb 3, 1998·Molecular and Cellular Biology·A S Lundberg, R A Weinberg
Mar 5, 1998·Nature·A FireC C Mello
Apr 18, 2003·Toxicology·Emma J BeddowesJ Kevin Chipman
Jun 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Lars ZenderStefan Kubicka
Aug 19, 2003·Nature Genetics·Sagrario OrtegaMariano Barbacid
Aug 28, 2003·Cell·Yan GengPiotr Sicinski
Sep 13, 2003·The EMBO Journal·Tiziana ParisiBruno Amati
Oct 17, 2003·Current Biology : CB·Cyril BerthetPhilipp Kaldis
Sep 1, 2007·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Mary K ManibusanDavid A Eastmond
Dec 7, 2007·Trends in Pharmacological Sciences·Marcos MalumbresJames R Bischoff
Apr 1, 2008·Nature Biotechnology·Yasushi SatoYoshiro Niitsu
May 19, 2009·Gastroenterology·Yulia A NevzorovaChristian Liedtke
Nov 16, 2010·Annual Review of Pathology·Virginia Hernandez-Gea, Scott L Friedman
May 14, 2011·Science·Stephen J JenkinsJudith E Allen
Dec 14, 2011·Expert Review of Gastroenterology & Hepatology·Frank Tacke, Ralf Weiskirchen
Mar 29, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yulia A NevzorovaChristian Liedtke
Jun 5, 2012·Current Biology : CB·Yuichiro MiyaokaAtsushi Miyajima
Jun 22, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Wei HuChristian Liedtke
Jan 15, 2014·Journal of Hepatology·Frank Tacke, Henning W Zimmermann
Apr 4, 2015·Laboratory Animals·D ScholtenR Weiskirchen
Jun 23, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Carolina Jiménez CalventeDetlef Schuppan
Aug 19, 2015·Nature Reviews. Genetics·Anders Wittrup, Judy Lieberman
Nov 12, 2015·Journal of Hepatology·Akiko EguchiAriel E Feldstein
Dec 3, 2015·Advanced Healthcare Materials·Leonard KapsRudolf Zentel
Citations
Dec 22, 2017·Expert Opinion on Biological Therapy·Mohube Betty MaepaPatrick Arbuthnot
Apr 17, 2019·Animals : an Open Access Journal From MDPI·Simone KumstelDietmar Zechner
May 24, 2019·Immunopharmacology and Immunotoxicology·Shengwang WuXia Gong
Nov 24, 2019·Hepatology International·Jing ZhaoJun Cheng
Mar 20, 2018·Oncogene·Haksier EhedegoChristian Trautwein
Mar 30, 2019·PeerJ·Zhu ZhanMingli Peng
Aug 29, 2018·Proceedings of the National Academy of Sciences of the United States of America·Roland SonntagChristian Liedtke
Sep 14, 2018·Frontiers in Pharmacology·Xin FengGe-Jia Zhong
Oct 23, 2019·Cells·Kateryna LevadaMatthias Bartneck
Jul 23, 2020·Frontiers in Immunology·Lei HouLiying Li
May 10, 2020·International Journal of Molecular Sciences·Anna HübbersChristian Liedtke
Dec 17, 2019·Drug Discovery Today·Solomon TadesseShudong Wang
Mar 29, 2021·Advanced Drug Delivery Reviews·Matthias Bartneck
Mar 30, 2021·Bioorganic & Medicinal Chemistry Letters·Jin-Ping WangJi-Jun Chen
Nov 21, 2020·Journal of Hepatology·Huaxin ChenQi Zhang
Apr 18, 2021·British Journal of Pharmacology·Xiaoyun ZhuLingyi Kong
May 31, 2021·Trends in Cell Biology·Chen ChuPiotr Sicinski
Jul 9, 2021·ACS Central Science·Jiajing GuoYuan Ping
Jun 19, 2021·Advanced Science·Ke CaoJiankang Liu