Kupffer cells and not liver sinusoidal endothelial cells prevent lentiviral transduction of hepatocytes

被引:39
作者
van Til, NP
Markusic, DM
van der Rijt, R
Kunne, C
Hiralall, JK
Vreeling, H
Frederiks, WM
Oude-Elferink, RPJ
Seppen, J
机构
[1] AMC, Ctr Liver, NL-1105 BK Amsterdam, Netherlands
[2] Acad Med Ctr, Dept Cell Biol & Histol, Amsterdam, Netherlands
关键词
lentiviral vectors; gene transfer; GFP; liver; hepatocytes; Kupffer cells; sinusoidal endothelial cells;
D O I
10.1016/j.ymthe.2004.09.012
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Lentiviral vectors can stably transduce dividing and nondividing cells in vivo and are best suited to long-term correction of inherited liver diseases. Intraportal administration of lentiviral vectors expressing green fluorescent protein (Lenti-GFP) in mice resulted in a higher transduction of nonparenchymal cells than hepatocytes (7.32 +/- 3.66% vs 0.22 +/- 0.08%, respectively). Therefore, various treatments were explored to increase lentiviral transduction of hepatocytes. Lenti-GFP was injected into the common bile duct, which led to transduction of biliary epithelium and hepatocytes at low efficiency. Transient removal of the sinusoidal endothelial cell layer by cyclophosphamide to increase accessibility to hepatocytes did not improve hepatocyte transduction (0.42 +/- 0.36%). Inhibition of Kupffer cell function by gadolinium chloride led to a significant decrease in GFP-positive nonparenchymal cells (2.15 +/- 3.14%) and a sevenfold increase in GFP-positive hepatocytes compared to nonpretreated mice (1.48 +/- 2.01%). These findings suggest that sinusoidal endothelial cells do not significantly limit lentiviral transduction of hepatocytes, while Kupffer cells sequester lentiviral particles thereby preventing hepatocyte transduction. Therefore, the use of agents that inhibit Kupffer cell function may be important for lentiviral vector treatment of liver disease.
引用
收藏
页码:26 / 34
页数:9
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