Functional human hepatocytes xeno-engrafted in mouse liver can be used as a model system to study hepatitis virus infection and vaccine efficacy. Significant liver xeno-repopulation has been reported in two kinds of genetically modified mice that have both immune deficiency and liver injury-induced donor hepatocyte selection: the uPA/SCID mice and Fah -/- Rag2-/-Il2rg-/- mice. The lack of hardy breeding and the overly elaborated technique in these two models may hinder the potential future application of these models to hepatitis virus infection and vaccination studies. Improving the transplantation protocol for liver xeno-repopulation from human hepatocytes will increase the model efficiency and application. In this study, we successfully apply immunosuppressive drug treatments of anti-asialo GM1 and FK506 in Fah-/-Rag2-/- mice, resulting in significant liver xeno-repopulation from human hepatocytes and human fetal liver cells. This methodology decreases the risk of animal mortality during breeding and surgery. When infected with hepatitis B virus (HBV) sera, Fah-/-Rag2-/- mice with liver xeno-repopulation from human hepatocytes accumulate significant levels of HBV DNA and HBV proteins. Our new protocol for humanized liver could be applied in the study of human hepatitis virus infection in vivo, as well as the pharmacokinetics and efficacy of potential vaccines.
Bibliographical noteFunding Information:
Supported by National Natural Science Foundation of China ( 30623003, 30700400, 30801115, 30901449 ), National Key Basic Research and Development Program of China ( 2007CB947903, 2009CB941100, 2010CB945602 ), Chinese National 863 Plan Project ( 2006AA02Z474 ), The Chinese Academy of Sciences ( KSCX2-YW-R-49 ), The Council of Shanghai Municipal Government for Science and Technology ( 07JC14067 ), China Postdoctoral Science Foundation ( 20070410743 ), and National Institutes of Health Grant ( DK074561 and AI065565, to X.W. ).
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