title: Foxf1 siRNA delivery to hepatic stellate cells by DBTC lipoplex formulations ameliorates fibrosis in livers of bile duct ligated mice.
abstract: Activation of hepatic stellate cells (HSCs) is a key event in pathogenesis of liver fibrosis and represents an orchestral interplay of inhibiting and activating transcription factors like forkhead box f1 (Foxf1), being described to stimulate pro-fibrogenic genes in HSCs. Here, we evaluated a lipidbased liver-specific delivery system (DBTC) suitable to transfer Foxf1 siRNA specifically to HSCs and examined its antifibrotic potential on primary HSCs and LX-2 cells as well as in a murine model of bile duct ligation (BDL)-induced secondary cholestasis. Foxf1 silencing reduced proliferation capacity and attenuated contractility of HSCs. Systemic administration of DBTC-lipoplexes in mice was sufficient to specifically silence genes expressed in different liver cell types. Using intravital and immunofluorescence microscopy we confirmed the specific delivery of Cy3-labeled DBTC to the liver, and particularly to HSCs. Repeated treatment with DBTC-lipoplexes resulted in siRNA-mediated silencing of Foxf1 early after BDL and finally attenuated progression of the fibrotic process. Decreased HSC activation in-effect ameliorated liver injury as shown by substantial reduction of necrotic area and deposition of extracellular matrix. Our findings suggest that Foxf1 may serve as a target gene to disrupt progression of liver fibrosis and DBTC might provide a potentially feasible and effective tool for HSC-specific delivery of therapeutic RNA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.forename: Malte
authors.initials: M
authors.lastname: Brensel
authors.forename: Berit
authors.initials: B
authors.lastname: Genz
authors.forename: Kira
authors.initials: K
authors.lastname: Roth
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.forename: Volker
authors.initials: V
authors.lastname: Fehring
authors.forename: Ute
authors.initials: U
authors.lastname: Schaeper
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany. kerstin.abshagen@uni-rostock.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery*; D004337:Drug Carriers; D051858:Forkhead Transcription Factors / Q000235:genetics*; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000517:prevention & control*; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D004337:Drug Carriers; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D034741:RNA, Small Interfering