logo

Chinese Science Bulletin, Volume 64, Issue 30: 3070-3076(2019) https://doi.org/10.1360/N972019-00303

Humanized mouse models for human viral hepatitis and related liver diseases

More info
  • ReceivedApr 9, 2019
  • AcceptedMay 8, 2019
  • PublishedJun 13, 2019

Abstract

Liver diseases, such as viral hepatitis and related fibrosis, cirrhosis and hepatocellular carcinomas, greatly threaten the health of human beings and constitute a global health problem. Nevertheless, suitable animal models of human liver diseases, especially for hepatitis virus infections, are not yet successfully established to avoid the defects of the traditional animal models. Take hepatitis B virus (HBV)and hepatitis C virus (HCV) for examples, most of the existing experimental animals except chimpanzee and Tupaia belangeri, cannot form a natural infection of these two hepatitis viruses, because of the stringent host species barrier to the infection. Human and chimpanzee hepatocytes are natural target cells for HBV and HCV infections and susceptible to infections of these two hepatitis viruses, which suggests that virus-specific receptors on the surface of these hepatocytes, as well as the intrinsic cellular circumstances, can support the initiation of the infection and the whole intracellular life cycle of hepatitis B and C viruses. Therefore, although chimpanzee is a costly animal model, it was used to study HBV and HCV infections and host immunological responses, especially to analyze natural and adaptive immune responses to infection. Though regarded as a high standard non-human primate model for hepatitis virus infection, chimpanzees have already been banned to use for experiments in Europe and the United States because of ethical concerns. Mice are convenient and cheap laboratory animals, but they cannot be infected by HBV naturally. Transgenic mice expressing partial or complete viral genomes are useful to study viral replication, yet the viral life cycles are incomplete and virus-host interaction, especially the host immunological responses against the viruses, cannot be investigated due to the immunological tolerance to the transgenes.

To overcome these limitations, humanized mouse models have been developed. Humanized mouse models, in which the liver is engrafted with human hepatocytes, can veritably mimic human infection cases, and thus play important roles in the research on human viral hepatitis and related liver diseases. They can be applied also to evaluate vaccination strategies, drug metabolism, personalized medical treatment, hence has become a popular option of pre-clinical animal models. The development of humanized mouse models for liver diseases have gone through several stages, from human liver chimeric mouse (e.g., uPA/SCID, FRG, TK-NOG, and Alb-TRECK/SCID) to humanized liver and immune system double chimeric mouse (e.g., AFC8, FRGN, uPA/NOG, and FRGS), and further to hepatitis virus-infected models based on these humanized mice. So far, humanized mouse models represent the summit models for the in vivo studies of hepatitis virus infections. These humanized mouse models have their advantages and disadvantages, which should be carefully assessed on the basis of the specific research aims. This review summarizes several important humanized mouse models which are used in the field of human liver disease researches. Great progress has been made in humanized mouse models over the past years, however, these models are still under development. In the future, better-humanized mouse models can be anticipated for further research of antiviral treatments, virus-host interactions and novel immunotherapies for human liver diseases.


Funded by

国家科技重大专项(2017ZX10304402-001-012,2017ZX10304402-001-006)


References

[1] Allweiss L, Dandri M. Experimental in vitro and in vivo models for the study of human hepatitis B virus infection. J Hepatol, 2016, 64: S17-S31 CrossRef PubMed Google Scholar

[2] Rhim J A, Sandgren E P, Degen J L, et al. Replacement of diseased mouse liver by hepatic cell transplantation. Science, 1994, 263: 1149-1152 CrossRef ADS Google Scholar

[3] Song X, Guo Y, Duo S, et al. A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation. Am J Pathol, 2009, 175: 1975-1983 CrossRef PubMed Google Scholar

[4] Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol, 2007, 25: 903-910 CrossRef PubMed Google Scholar

[5] Hasegawa M, Kawai K, Mitsui T, et al. The reconstituted “humanized liver” in TK-NOG mice is mature and functional. Biochem BioPhys Res Commun, 2011, 405: 405-410 CrossRef PubMed Google Scholar

[6] Zhang R R, Zheng Y W, Li B, et al. Human hepatic stem cells transplanted into a fulminant hepatic failure Alb-TRECK/SCID mouse model exhibit liver reconstitution and drug metabolism capabilities. Stem Cell Res Ther, 2015, 6: 49 CrossRef PubMed Google Scholar

[7] Ren X N, Ren R R, Yang H, et al. Human liver chimeric mouse model based on diphtheria toxin-induced liver injury. WJG, 2017, 23: 4935-4941 CrossRef PubMed Google Scholar

[8] Washburn M L, Bility M T, Zhang L, et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology, 2011, 140: 1334-1344 CrossRef PubMed Google Scholar

[9] Wilson E M, Bial J, Tarlow B, et al. Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Res, 2014, 13: 404-412 CrossRef PubMed Google Scholar

[10] Gutti T L, Knibbe J S, Makarov E, et al. Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. Am J Pathol, 2014, 184: 101-109 CrossRef PubMed Google Scholar

[11] Yuan L, Jiang J, Liu X, et al. HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation. Gut, 2019, doi: 10.1136/gutjnl-2018-316091. Google Scholar

[12] Hwang J R, Park S G. Mouse models for hepatitis B virus research. Lab Anim Res, 2018, 34: 85-91 CrossRef PubMed Google Scholar

[13] Allweiss L, Volz T, Lütgehetmann M, et al. Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration. J Hepatol, 2014, 60: 500-507 CrossRef PubMed Google Scholar

[14] Ishida Y, Chung T L, Imamura M, et al. Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics. Hepatology, 2018, 68: 473-484 CrossRef PubMed Google Scholar

[15] Bility M T, Cheng L, Zhang Z, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: Induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog, 2014, 10: e1004032 CrossRef PubMed Google Scholar

[16] Dusséaux M, Masse-Ranson G, Darche S, et al. Viral load affects the immune response to HBV in mice with humanized immune system and liver. Gastroenterology, 2017, 153: 1647−1661. Google Scholar

[17] Shoukry N H. Hepatitis C vaccines, antibodies, and T cells. Front Immunol, 2018, 28: 1480. Google Scholar

[18] Mercer D F, Schiller D E, Elliott J F, et al. Hepatitis C virus replication in mice with chimeric human livers. Nat Med, 2001, 7: 927-933 CrossRef PubMed Google Scholar

[19] Bissig K D, Wieland S F, Tran P, et al. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest, 2010, 120: 924-930 CrossRef PubMed Google Scholar

[20] Keng C T, Sze C W, Zheng D, et al. Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection. Gut, 2016, 65: 1744-1753 CrossRef PubMed Google Scholar

[21] Ji C, Liu Y, Pamulapati C, et al. Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody. Hepatology, 2015, 61: 1136−1144. Google Scholar

[22] Sureau C, Negro F. The hepatitis delta virus: Replication and pathogenesis. J Hepatol, 2016, 64: S102-S116 CrossRef PubMed Google Scholar

[23] Lütgehetmann M, Mancke L V, Volz T, et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology, 2012, 55: 685-694 CrossRef PubMed Google Scholar

[24] Giersch K, Allweiss L, Volz T, et al. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol, 2015, 63: 346-353 CrossRef PubMed Google Scholar

[25] Giersch K, Homs M, Volz T, et al. Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice. Sci Rep, 2017, 7: 3757 CrossRef PubMed ADS Google Scholar

[26] Kamar N, Izopet J, Pavio N, et al. Hepatitis E virus infection. Nat Rev Dis Primers, 2017, 3: 17086 CrossRef PubMed Google Scholar

[27] Allweiss L, Gass S, Giersch K, et al. Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation. J Hepatol, 2016, 64: 1033-1040 CrossRef PubMed Google Scholar

[28] Sayed I M, Foquet L, Verhoye L, et al. Transmission of hepatitis E virus infection to human-liver chimeric FRG mice using patient plasma. Antiviral Res, 2017, 141: 150-154 CrossRef PubMed Google Scholar

[29] Katoh M, Matsui T, Nakajima M, et al. Expression of human cytochromes P450 in chimeric mice with humanized liver. Drug Metab Dispos, 2004, 32: 1402-1410 CrossRef PubMed Google Scholar

[30] Nishimura T, Nishimura T, Hu Y, et al. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Therapeut, 2013, 344: 388-396 CrossRef PubMed Google Scholar

[31] Xu D, Michie S A, Zheng M, et al. Humanized thymidine kinase-NOG mice can be used to identify drugs that cause animal-specific hepatotoxicity: A case study with furosemide. J Pharmacol Exp Therapeut, 2015, 354: 73-78 CrossRef PubMed Google Scholar

[32] Xu D, Wu M, Nishimura S, et al. Chimeric TK-NOG mice: A predictive model for cholestatic human liver toxicity. J Pharmacol Exp Therapeut, 2015, 352: 274-280 CrossRef PubMed Google Scholar

  • Table 1   Liver chimeric mouse models

    模型

    肝脏损伤的原因

    肝脏损伤的控制方式

    优势

    缺点

    uPA/SCID

    uPA的表达

    无法控制

    重建效率高

    无法控制肝损程度与时机, 无法进行免疫学研究

    FRG

    Fah的缺乏

    NTBC

    肝损程度可控

    无法进行免疫学研究

    TK-NOG

    HSVtk

    GSV

    肝损程度可控

    无法进行免疫学研究

    Alb-TRECK/SCID

    人HB-EGF样受体

    DT

    肝损程度可控

    无法进行免疫学研究

  • Table 2   Liver and immune system double chimeric mouse

    模型

    肝脏损伤的原因

    肝脏损伤的控制方式

    免疫缺陷背景

    优势

    缺点

    AFC8

    AFC8

    AP20187

    IL2rg–/– Rag2–/–

    可用于病毒感染后的免疫学相关研究

    病毒感染效率较低

    FRGN

    Fah的缺乏

    NTBC

    IL2rg–/– Rag2–/–

    uPA/NOG

    uPA的表达

    无法控制

    NOG

    FRGS

    Fah的缺乏

    NTBC

    IL2RγC–/–Rag2–/–SCID

Copyright 2020 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有

京ICP备18024590号-1