Transduction of Liver Nonparenchymal Cells by Hydrodynamic Tail Vein Injection of Plasmid DNA

Hydrodynamic tail vein (HTV) injection of plasmid DNA is a powerful tool for gene transfer to the mouse liver. It consists of a rapid injection in about 5 seconds via tail vein of a physiological solution containing plasmid DNA, equivalent in volume to 8-10% of body weight. All the data published so far reported that expression derived from HTV delivery of plasmid was limited to hepatocytes. To fully characterize the repertoire of transduced liver cells, and taking advantage of the use of sensitive techniques such as specific immunohis-tochemical analysis, flow cytometry and PCR, we analyzed whether other liver cell types could also be transfected and express the transgene after HTV injection. We show here for the first time that, in addition to hepatocytes, other hepatic cells were also transduced after the hydrodynamic injection of a plasmid encoding a reporter gene. In particular, a significant percentage of nonparenchymal immune liver cells were transduced, including Kupffer and dendritic cells, which are the main hepatic antigen presenting cells (APCs). Importantly, RT-PCR analysis confirmed that these cells were expressing the transgene. Hepatic APCs form a natural, tolerogenic microenvironment in the liver. Thus, our data may have implications for the design of new immunomodulatory liver-targeted gene therapy approaches to treat inflammatory or autoimmune diseases by specifically targeting these cells. At present, we are investigating the potential of this approach to treat type 1 diabetes using several candidate genes.