Abstract
Functional human hepatocytes xenografted into the liver of mice can be used as a model system to study pharmacokinetics, infection of hepatitis viruses, and the efficacy of hepatitis vaccines. Significant levels of liver xeno-repopulation have been reported in Fah−/−Rag2−/−Il2rg−/− mice. However, the high mortality and low breeding rate of this model may hinder its application. A new model, termed Fah−/−Nod/Scid mice, which combines the advantages of liver repopulation in Fah−/− mice with the ease of xenotransplantation in Nod/Scid mice was obtained by gradual cross-breeding. Fah−/−Nod/Scid mice were easily maintained in breeding colonies and in adult animal care facilities. FK506 treatment combined with gradual withdrawal of NTBC before cell transplantation ensured that Fah−/−Nod/Scid mice were susceptible to liver xeno-repopulation by human hepatocytes; the proportion of engrafted human hepatocytes reached 33.6%. The function of the expanded human hepatocytes within the chimeric liver was confirmed by weight curve analysis, the expression of characteristic proteins, and the biochemical analysis of liver function. These results show that Fah−/−Nod/Scid mice are an ideal humanized liver mouse model with many useful applications.
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Meuleman P, Libbrecht L, De Vos R, et al. Morphological and biochemical characterization of a human liver in an uPA-SCID mouse chimera. Hepatology, 2005, 41: 847–856, 15791625, 10.1002/hep.20657, 1:CAS:528:DC%2BD2MXjsV2msLc%3D
Dandri M, Burda M R, Török E, et al. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology, 2001, 33: 981–988, 11283864, 10.1053/jhep.2001.23314, 1:STN:280:DC%2BD3M3ivVOqtw%3D%3D
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, 11479625, 10.1038/90968, 1:CAS:528:DC%2BD3MXlvVOktrg%3D
Vanwolleghem T, Bukh J, Meuleman P, et al. Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver-chimeric mice from infection with a homologous hepatitis C virus strain. Hepatology, 2008, 47: 1846–1855, 18452146, 10.1002/hep.22244, 1:CAS:528:DC%2BD1cXotVagtr8%3D
Sugiyama M, Tanaka Y, Kurbanov F, et al. Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes. Gastroenterology, 2009, 136: 652–662, 19041311, 10.1053/j.gastro.2008.10.048, 1:CAS:528:DC%2BD1MXislOhtbs%3D
Dandri M, Murray J M, Lutgehetmann M, et al. Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia. Hepatology, 2008, 48: 1079–1086, 18697217, 10.1002/hep.22469
Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol, 2007, 25: 903–910, 17664939, 10.1038/nbt1326, 1:CAS:528:DC%2BD2sXos12ntb4%3D
Bissig K D, Le T T, Woods N B, et al. Repopulation of adult and neonatal mice with human hepatocytes: A chimeric animal model. Proc Natl Acad Sci USA, 2007, 104: 20507–20511, 18077355, 10.1073/pnas.0710528105, 1:CAS:528:DC%2BD1cXjsleltg%3D%3D
He Z Y, Zhang H B, Zhang X, et al. Liver xeno-repopulation with human hepatocytes in Fah−/−Rag2−/− mice after pharmacological immunosuppression. Am J Pathol, 2010, 177: 1311–1319, 20651238, 10.2353/ajpath.2010.091154, 1:CAS:528:DC%2BC3cXht1KmsbzL
Grompe M, al-Dhalimy M, Finegold M, et al. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev, 1993, 12: 2298–2307, 10.1101/gad.7.12a.2298
Overturf K, al-Dhalimy M, Ou C N, et al. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol, 1997, 151: 1273–1280, 9358753, 1:STN:280:DyaK1c%2FitlKntw%3D%3D
Wang X, Montini E, Al-Dhalimy M, et al. Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol, 2002, 161: 565–574, 12163381, 10.1016/S0002-9440(10)64212-5
Wang X, Foster M, Al-Dhalimy M, et al. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA, 2003, 100: 11881–11888, 12902545, 10.1073/pnas.1734199100, 1:CAS:528:DC%2BD3sXotFSmtb4%3D
Shultz L D, Schweitzer P A, Christianson S W, et al. Multiple defects of innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol, 1995, 154: 180–191, 7995938, 1:CAS:528:DyaK2MXivVShu7g%3D
Wilber A, Wangensteen K J, Chen Y, et al. Messenger RNA as a source of transposase for sleeping beauty transposon-mediated correction of hereditary tyrosinemia type I. Mol Ther, 2007, 15: 1280–1287, 17440442, 10.1038/sj.mt.6300160, 1:CAS:528:DC%2BD2sXhtVejtL3F
Tateno C, Yoshizane Y, Saito N, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol, 2004, 165: 901–912, 15331414, 10.1016/S0002-9440(10)63352-4, 1:CAS:528:DC%2BD2cXnvFKit74%3D
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, 8108734, 10.1126/science.8108734, 1:STN:280:DyaK2c7ltFKrtQ%3D%3D
Escribano O, Fernández-Moreno M D, Piña M J, et al. Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver. Hepatology, 2002, 36: 555–561, 12198647, 10.1053/jhep.2002.35439, 1:CAS:528:DC%2BD38XnvVSkt70%3D
Kawamura I, Takeshita S, Fushimi M, et al. Induction of choleresis by inmunosuppressant FK506 through stimulation of insulin-like growth factor I production in the liver of rats. Eur J Pharmacol, 2001, 419: 99–105, 11348636, 10.1016/S0014-2999(01)00961-X, 1:CAS:528:DC%2BD3MXjtlChtbs%3D
Tanaka N, Yamamoto H, Tatemoto A, et al. Regulation of liver regeneration by interleukin-2 and its inhibitors: Cyclosporin A and FK506. Int J Immunopharmacol, 1993, 15: 211–218, 7682200, 10.1016/0192-0561(93)90097-I, 1:CAS:528:DyaK3sXitFWis7s%3D
Thomale U W, Bender M, Casalis P, et al. Tacrolimus depresses local immune cell infiltration but fails to reduce cortical contusion volume in brain-injured rats. Immunobiology, 2007, 212: 567–576, 17678714, 10.1016/j.imbio.2007.01.007, 1:CAS:528:DC%2BD2sXhtV2nsbvP
Setkowicz Z, Caryk M, Szafraniec M, et al. Tacrolimus (FK506) and cyclosporin A reduce macrophage recruitment to the rat brain injured at perinatal and early postnatal periods. Neurol Res, 2009, 31: 1060–1067, 19138474, 10.1179/174313209X383295, 1:CAS:528:DC%2BC3cXisVGjtg%3D%3D
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Su, B., Liu, C., Xiang, D. et al. Xeno-repopulation of Fah−/−Nod/Scid mice livers by human hepatocytes. Sci. China Life Sci. 54, 227–234 (2011). https://doi.org/10.1007/s11427-011-4140-7
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DOI: https://doi.org/10.1007/s11427-011-4140-7