Human hepatocytes can repopulate mouse liver: histopathology of the liver in human hepatocyte-transplanted chimeric mice and toxicologic responses to acetaminophen.
A human hepatocyte-transplanted chimeric mouse has been established by transplantation of human hepatocytes to urokinase-type plasminogen activator transgenic/severe combined immunodeficiency (uPA(+/+)/SCID) mice. These chimeric mice have various amounts of human hepatocytes that proliferate extensively and progressively replace mouse hepatocytes. In the chimeric liver, hepatic cords and sinusoid-like structures were observed. The human hepatocytes expressed human albumin, human cytochrome P450 enzymes, and human transporter proteins. Furthermore, electron microscopic analysis demonstrated bile canaliculi associated with human hepatocytes in the chimeric mouse livers. These results indicate that the chimeric mouse livers contain functionally intact and differentiated human hepatocytes. Additionally, the toxicologic response of hepatocytes to acetaminophen (APAP) administration was compared in normal and chimeric mouse livers. Following 1,400 mg/kg APAP, mild hepatocellular degeneration was observed in the human hepatocyte areas in the chimeric mice, compared with severe centrilobular hepatocellular necrosis in the ICR mouse livers. In conclusion, these chimeric livers contain functionally differentiated human hepatocytes, and are less susceptible to APAP toxicity, compared to ICR mice.
Sato
Yasushi
Y
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Chita-gun, Aichi, Japan. yasushi.sato@po.rd.taisho.co.jp
Yamada
Hiroshi
H
Iwasaki
Kazuhide
K
Tateno
Chise
C
Yokoi
Tsuyoshi
T
Yoshizato
Katsutoshi
K
Horii
Ikuo
I
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009336:Necrosis; D018183:Transplantation Chimera; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D014568:Urokinase-Type Plasminogen Activator