Foxf1 siRNA Delivery to Hepatic Stellate Cells by DBTC Lipoplex Formulations Ameliorates Fibrosis in Livers of Bile Duct Ligated Mice
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.
Keywords: Cholestasis, chronic liver disease, intravital microscopy, lipoplex, mouse, silencing.
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