title: Hepatic stellate cell-targeted delivery of hepatocyte growth factor transgene via bile duct infusion enhances its expression at fibrotic foci to regress dimethylnitrosamine-induced liver fibrosis.
abstract: Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A-coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The antifibrotic effects of DsRed2-HGF vector encapsulated within vitamin A-coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-β1. In rats, dimethylnitrosamine-induced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus, targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its antifibrotic effects.
authors.affiliation: NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Republic of Singapore .
authors.forename: Balakrishnan Chakrapani
authors.initials: BC
authors.lastname: Narmada
authors.forename: Yuzhan
authors.initials: Y
authors.lastname: Kang
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Venkatraman
authors.forename: Qiwen
authors.initials: Q
authors.lastname: Peng
authors.forename: Rashidah Binte
authors.initials: RB
authors.lastname: Sakban
authors.forename: Bramasta
authors.initials: B
authors.lastname: Nugraha
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.forename: Peter T C
authors.initials: PT
authors.lastname: So
authors.forename: Lisa
authors.initials: L
authors.lastname: Tucker-Kellogg
authors.forename: Hai-Quan
authors.initials: HQ
authors.lastname: Mao
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001652:Bile Ducts; D004128:Dimethylnitrosamine / Q000633:toxicity; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D055166:Hepatic Stellate Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes / Q000627:therapeutic use; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy*; D051381:Rats; D019076:Transgenes
chemical_list: D008081:Liposomes; D017228:Hepatocyte Growth Factor; D004128:Dimethylnitrosamine