Research Article: An inducible human LDLR transgenic mouse model for enhanced lentiviral gene delivery to murine immune cells
Abstract:
Lentivirus (LV)-based manipulation of immune cells is a commonly used approach in cell therapies. However, the most frequently used Vesicular Stomatitis Virus Glycoprotein (VSV-G) pseudotyping approach is inefficient to support LV gene delivery of mouse immune cells due to the lack of an optimal entry receptor. Here, we present a transgenic mouse model with Cre recombinase-inducible expression of the human Low Density Lipoprotein Receptor (hLDLR), the natural entry receptor of VSV-G LV. Surprisingly, we found that Cre induces robust hLDLR expression across multiple immune cells only under activation conditions. Induction of hLDLR expression by genetic crossing with Cre-transgenic mice or exposure to Cre mRNA-lipid nanoparticles (LNPs) potently sensitized murine immune cells, especially T cells, to VSV-G LV-mediated gene delivery. This novel transgenic mouse model serves as a valuable tool for investigating immune cell function and engineered cell therapies for cancer in syngeneic mouse models.
Introduction:
Efficient genetic manipulation of mouse immune cells, including T-cells, is critical to accurately investigate new immunotherapies as well as to interrogate the mechanism of existing therapies in immunocompetent mouse models ( 1 , 2 ). A number of methods have been used for genetic engineering of mouse immune cells, especially T cells, such as viral vectors ( 3 ), electroporation ( 4 ), and lipid nanoparticles ( 5 ). Among these methods, lentivirus (LV) transduction has been the most widely used method, given its…
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