title: Human hepatic stem cells transplanted into a fulminant hepatic failure Alb-TRECK/SCID mouse model exhibit liver reconstitution and drug metabolism capabilities.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  1.5 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.
  
  
  RESULTS
  Both 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. ranranzhang.0537@hotmail.com.
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Zhang
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. ywzheng@md.tsukuba.ac.jp.|Department of Advanced Gastroenterological Surgical Science and Technology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan. ywzheng@md.tsukuba.ac.jp.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Zheng
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, 97239, USA. libi@ohsu.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. rusticanatt@kra.biglobe.ne.jp.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsuchida
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. uenoy@yokohama-cu.ac.jp.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. nie.yunzhong@gmail.com.
authors.forename: Yun-Zhong
authors.initials: YZ
authors.lastname: Nie
authors.affiliation: Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. rtanigu@med.yokohama-cu.ac.jp.|Advanced Medical Research Center, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. rtanigu@med.yokohama-cu.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002678:Chimera; D003647:Debrisoquin / Q000378:metabolism; D004167:Diphtheria Toxin / Q000008:administration & dosage; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D007660:Ketoprofen / Q000378:metabolism; D008099:Liver / Q000166:cytology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D004167:Diphtheria Toxin; D007660:Ketoprofen; D003647:Debrisoquin