Liver xeno-repopulation with human hepatocytes in Fah -/-Rag2-/- mice after pharmacological immunosuppression

Zhiying He; Haibin Zhang; Xin Zhang; Dongfu Xie; Yixin Chen; Kirk J. Wangensteen; Stephen C. Ekker; Meri Firpo; Changcheng Liu; Dao Xiang; Xiaoyuan Zi; Lijian Hui; Guangshun Yang; Xiaoyan Ding; Yiping Hu; Xin Wang

doi:10.2353/ajpath.2010.091154

Liver xeno-repopulation with human hepatocytes in Fah ^-/-Rag2^-/- mice after pharmacological immunosuppression

Zhiying He, Haibin Zhang, Xin Zhang, Dongfu Xie, Yixin Chen, Kirk J. Wangensteen, Stephen C. Ekker, Meri Firpo, Changcheng Liu, Dao Xiang, Xiaoyuan Zi, Lijian Hui, Guangshun Yang, Xiaoyan Ding, Yiping Hu, Xin Wang

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1311-1319
Number of pages	9
Journal	American Journal of Pathology
Volume	177
Issue number	3
DOIs	https://doi.org/10.2353/ajpath.2010.091154
State	Published - Sep 2010

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.2353/ajpath.2010.091154

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He, Z., Zhang, H., Zhang, X., Xie, D., Chen, Y., Wangensteen, K. J., Ekker, S. C., Firpo, M., Liu, C., Xiang, D., Zi, X., Hui, L., Yang, G., Ding, X., Hu, Y., & Wang, X. (2010). Liver xeno-repopulation with human hepatocytes in Fah ^-/-Rag2^-/- mice after pharmacological immunosuppression. American Journal of Pathology, 177(3), 1311-1319. https://doi.org/10.2353/ajpath.2010.091154

He, Z, Zhang, H, Zhang, X, Xie, D, Chen, Y, Wangensteen, KJ, Ekker, SC, Firpo, M, Liu, C, Xiang, D, Zi, X, Hui, L, Yang, G, Ding, X, Hu, Y & Wang, X 2010, 'Liver xeno-repopulation with human hepatocytes in Fah ^-/-Rag2^-/- mice after pharmacological immunosuppression', American Journal of Pathology, vol. 177, no. 3, pp. 1311-1319. https://doi.org/10.2353/ajpath.2010.091154

@article{3529fbb50f964f9ab9c5cee81cefd780,

title = "Liver xeno-repopulation with human hepatocytes in Fah -/-Rag2-/- mice after pharmacological immunosuppression",

abstract = "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.",

author = "Zhiying He and Haibin Zhang and Xin Zhang and Dongfu Xie and Yixin Chen and Wangensteen, {Kirk J.} and Ekker, {Stephen C.} and Meri Firpo and Changcheng Liu and Dao Xiang and Xiaoyuan Zi and Lijian Hui and Guangshun Yang and Xiaoyan Ding and Yiping Hu and Xin Wang",

note = "Funding 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. ). ",

year = "2010",

month = sep,

doi = "10.2353/ajpath.2010.091154",

language = "English (US)",

volume = "177",

pages = "1311--1319",

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T1 - Liver xeno-repopulation with human hepatocytes in Fah -/-Rag2-/- mice after pharmacological immunosuppression

AU - He, Zhiying

AU - Zhang, Haibin

AU - Zhang, Xin

AU - Xie, Dongfu

AU - Chen, Yixin

AU - Wangensteen, Kirk J.

AU - Ekker, Stephen C.

AU - Firpo, Meri

AU - Liu, Changcheng

AU - Xiang, Dao

AU - Zi, Xiaoyuan

AU - Hui, Lijian

AU - Yang, Guangshun

AU - Ding, Xiaoyan

AU - Hu, Yiping

AU - Wang, Xin

N1 - Funding 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. ).

PY - 2010/9

Y1 - 2010/9

N2 - 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.

AB - 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.

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Liver xeno-repopulation with human hepatocytes in Fah ^-/-Rag2^-/- mice after pharmacological immunosuppression

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