Human gene expression in Humanized mice (CBX102). unidentified

Severely immunodeficient NOG mice are used as recipients for human tissue transplantation, which produces chimeric mice with various types of human tissue. We developed two different types of experimental in vivo platform that replaces mouse liver with functioning human liver tissue. To do this, a urokinase-type plasminogen activator (uPA) or HSV-thymidine kinase (TK) transgene was expressed within the liver of highly immunodeficient mice (uPA-NOG and TK-NOG, respectively). Mouse liver cells expressing uPA transgene were ablated spontaneously after 6 weeks of birth, and TK transgene were ablated after a brief exposure to a non-toxic dose of gancyclovir, and transplanted human liver cells were stably maintained within the liver without exogenous drug or immunosuppressive treatments (humanized mice). Microarrays (Affymetrix Gene Chip Human Genome U133 Plus 2.0 Array) were used to compare the profile of hepatic gene expression in humanized mice with donor human liver cells. Of the 54,613 probes analyzed on this microarray, only 8% (4,484) cross-hybridized with liver obtained from non-transgenic NOG mice. In contrast, mRNA in liver obtained from humanized uPA-NOG mice (approx. 25% were replaced by human cells: moderately humanized liver) and humanized TK-NOG mice (approx. over 80% were replaced by human cells: highly humanized liver) hybridized to 23% (12,803) and 35% (19,090) of the probes, respectively. Highly humanized liver was remarkably similar to the donor human liver cells of which mRNA hybridized to 41% (22,592) of the probes. After elimination of the cross-reactive probe sets, there was a very high level of correlation between the hepatic gene expression profiles of uPA-NOG or TK-NOG-derived humanized liver tissue and transplanted human donor cells (r = 0.7030 and 0.7219, respectively).