Targeting CCl4 -induced liver fibrosis by RNA interference-mediated inhibition of cyclin E1 in mice

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Jörg-Martin BangenChristian Liedtke

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

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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
Aug 29, 2018·Proceedings of the National Academy of Sciences of the United States of America·Roland SonntagChristian Liedtke
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