Abstract

IntroductionChimeric mice with humanized livers were recently established by transplanting human hepatocytes. This mouse model that is repopulated with functional human hepatocytes could be a useful tool for investigating human hepatic cell biology and drug metabolism and for other preclinical applications. Successfully transplanting human hepatocytes into mice requires that recipient mice with liver failure do not reject these human cells and provide a suitable microenvironment (supportive niche) to promote human donor cell expansion and differentiation. To overcome the limitations of current mouse models, we used Alb-TRECK/SCID mice for in vivo human immature hepatocyte differentiation and humanized liver generation.Methods1.5 μg/kg diphtheria toxin was administrated into 8-week-old Alb-TRECK/SCID mice, and the degree of liver damage was assessed by serum aspartate aminotransferase activity levels. Forty-eight hours later, mice livers were sampled for histological analyses, and the human donor cells were then transplanted into mice livers on the same day. Chimeric rate and survival rate after cell transplantation was evaluated. Expressions of human hepatic-related genes were detected. A human albumin enzyme-linked immunosorbent assay was performed after 50 days of transplantation. On day 60 after transplantation, drug metabolism was examined in mice.ResultsBoth human primary fetal liver cells and hepatic stem cells were successfully repopulated in the livers of Alb-TRECK/SCID mice that developed lethal fulminant hepatic failure after administering diphtheria toxin; the repopulation rate in some mice was nearly 100%. Compared with human primary fetal liver cells, human hepatic stem cell transplantation rescued Alb-TRECK/SCID mice with lethal fulminant hepatic failure, and human hepatic stem cell-derived humanized livers secreted more human albumin into mouse sera and also functioned as a “human liver” that could metabolize the drugs ketoprofen and debrisoquine.ConclusionOur model of a humanized liver in Alb-TRECK/SCID mice may provide for functional applications such as drug metabolism, drug to drug interactions, and promote other in vivo and in vitro studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0038-9) contains supplementary material, which is available to authorized users.

Highlights

  • Chimeric mice with humanized livers were recently established by transplanting human hepatocytes

  • On day 60 after transplantation, drug metabolism was examined in mice. Both human primary fetal liver cells and hepatic stem cells were successfully repopulated in the livers of Alb-toxin receptor mediated cell knockout (TRECK)/severe combined immunodeficiency (SCID) mice that developed lethal fulminant hepatic failure after administering diphtheria toxin; the repopulation rate in some mice was nearly 100%

  • Overall, we have shown that Alb-TRECK/SCID mice are an ideal model for induced lethal fulminant hepatic failure that could be used to study hepatocyte regeneration and liver disease development and facilitate in vivo human immature hepatocyte differentiation; it has the potential for human drug metabolism testing

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Summary

Introduction

Chimeric mice with humanized livers were recently established by transplanting human hepatocytes. This mouse model that is repopulated with functional human hepatocytes could be a useful tool for investigating human hepatic cell biology and drug metabolism and for other preclinical applications. It is quite often difficult to determine whether a potential drug poses any risks during development for clinical applications [2,3] To address this problem, “humanized” mouse livers were developed by growing human liver tissues inside mice [4,5,6]. These models exhibited responses to drugs similar to those of the human liver. Current mouse models used for humanized liver generation are primarily uPA+/+ (uroplasminogen activator) mice [4,7], Fah−/− (fumarylacetoacetate hydrolase) mice [6], and a recently reported TK-NOG (thymidine kinase) mouse

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