Near completely humanized liver in mice shows human-type metabolic responses to drugs.
Human hepatocytes were transplanted into urokinase-type plasminogen activator-transgenic SCID mice (uPA/SCID mice), which are immunodeficient and undergo liver failure. The transplanted cells were characterized in terms of their in vivo growth potential and functions. The human hepatocytes progressively repopulated the murine host liver. However, the recipients died when the replacement index (RI) of the human hepatocytes exceeded 50%. The hosts (chimeric mice) survived at RI >50% when treated with a drug that has anti-human complement factor activity, and these mice developed livers with RI values as high as 96%. In total, 36 chimeric mice were generated, and the rate of successful engraftment was as high as 92%. The yield of chimeric mice with RI >70% was 32%. The human hepatocytes in the murine host liver expressed mRNAs for a variety of human cytochrome P450 (hCYP) subtypes, in a manner that was similar to the donor liver. The mRNAs for hCYP3A4 and hCYP1A1/2 were induced in the liver in a CYP type-specific manner when the mice were treated with rifampicin and 3-methylcholanthrene, respectively. These results indicate that human hepatocytes that propagate in mice retain their normal pharmacological responses. We conclude that the chimeric mouse developed in the present study is a useful model for assessing the functions and pharmacological responses of human hepatocytes.
Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER), Hiroshima, Japan.
Chise
C
Tateno
Yasumi
Y
Yoshizane
Naomi
N
Saito
Miho
M
Kataoka
Rie
R
Utoh
Chihiro
C
Yamasaki
Asato
A
Tachibana
Yoshinori
Y
Soeno
Kinji
K
Asahina
Hiroshi
H
Hino
Toshimasa
T
Asahara
Tsuyoshi
T
Yokoi
Toshinori
T
Furukawa
Katsutoshi
K
Yoshizato
D000293:Adolescent; D000328:Adult; D000418:Albumins / Q000378:metabolism; D000818:Animals; D002648:Child; D002678:Chimera; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors; D015926:Complement C3a / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D017093:Liver Failure / Q000378:metabolism / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012293:Rifampin / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
D000418:Albumins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D008748:Methylcholanthrene; D015926:Complement C3a; D003577:Cytochrome P-450 Enzyme System; D050577:Complement C3-C5 Convertases; D014568:Urokinase-Type Plasminogen Activator; D012293:Rifampin