Proteoglycans mediate cationic liposome-DNA complex-based gene delivery in vitro and in vivo.
The factors controlling cationic liposome-DNA complex (CLDC)-based gene transfer in cells and in animals are poorly understood. We found that cell surface heparin/heparan sulfate-bearing proteoglycans mediate CLDC-based gene transfer and expression both in cultured cells and following intravenous gene delivery into animals. CLDC did not transfect Raji cells, which lack proteoglycans, but did efficiently transfect Raji cells stably transfected with the proteoglycan, syndecan-1. Fucoidan, heparin, or dextran sulfate, all of which are highly anionic polysaccharides, each blocked CLDC-mediated transfection both in cultured cells and following intravenous injection into mice, but had no effect on transfection by either recombinant adenovirus infection or electroporation. Intravenous pretreatment of mice with heparinases, which specifically cleave heparan sulfate molecules from cell surface proteoglycans, blocked intravenous, CLDC-mediated transfection in mice, confirming that proteoglycans mediate CLDC gene delivery in vivo. Modulation of proteoglycan expression may prove useful in controlling the efficiency of, as well as targeting the sites of, CLDC-based gene transfer in animals.
Mounkes
L C
LC
California Pacific Medical Research Institute, San Francisco, California 94115, USA.
Zhong
W
W
Cipres-Palacin
G
G
Heath
T D
TD
Debs
R J
RJ
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000493:pharmacokinetics*; D018274:Electroporation; D018014:Gene Transfer Techniques; D019763:Heparin Lyase / Q000494:pharmacology; D007275:Injections, Intravenous; D008081:Liposomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008854:Microscopy, Electron; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology; D011509:Proteoglycans / Q000494:pharmacology*; D053668:Syndecan-1; D053667:Syndecans; D014162:Transfection / Q000379:methods
D002412:Cations; D004247:DNA; D019763:Heparin Lyase; D008081:Liposomes; D008562:Membrane Glycoproteins; D000071228:Polyelectrolytes; D011108:Polymers; D011509:Proteoglycans; D053668:Syndecan-1; D053667:Syndecans; C508242:Sdc1 protein, mouse