Lipid emulsions potently increase transgene expression in hepatocytes after adenoviral transfer.
Elimination of Kupffer cells by cytotoxic clodronate liposomes increases transgene expression in the liver after adenoviral transfer. Here, we demonstrate that empty l-alpha-phosphatidylcholine liposomes block uptake of vectors in the reticuloendothelial cells of the liver and increase human apolipoprotein (apo) A-I (approved gene symbol apo A-I) expression in C57BL/6 (1.3-fold) and Balb/c mice (3.1-fold) to the same extent as clodronate liposomes (1.5- and 3.4-fold, respectively). A similar elevation of human apo A-I levels was induced by the lipid emulsion Intralipid (1.5- and 2.8-fold in C57BL/6 and Balb/c mice, respectively). Not only Kupffer cells but also hepatic sinusoidal endothelial cells (HSEC) constitute the reticuloendothelial cells of the liver. The uptake of adenoviral vectors 1 h after transfer in C57BL/6 mice was 2.9-fold lower in Kupffer cells than in HSEC. In contrast, Kupffer cell uptake in Balb/c mice was 2.6-fold higher than in HSEC. Vector uptake in reticuloendothelial cells of the liver was reduced and transgene expression was increased in splenectomized and Rag2-deficient Balb/c mice but not in splenectomized and Rag1-deficient C57BL/6 mice. In conclusion, lipid emulsions for parenteral clinical use block uptake of adenoviral vectors by the reticuloendothelial cells of the liver and potently increase transgene expression.
Snoeys
Jan
J
Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Mertens
Geertrui
G
Lievens
Joke
J
van Berkel
Theo
T
Collen
Désiré
D
Biessen
Erik A L
EA
De Geest
Bart
B
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D004002:Clodronic Acid / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005217:Fat Emulsions, Intravenous / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines / Q000737:chemistry / Q000494:pharmacology*; D013156:Splenectomy; D014161:Transduction, Genetic; D019076:Transgenes
D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D005217:Fat Emulsions, Intravenous; D018398:Homeodomain Proteins; D008081:Liposomes; D010713:Phosphatidylcholines; C499308:Rag2 protein, mouse; D004002:Clodronic Acid; C064658:RAG-1 protein