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Toxicologic Pathology
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Human Hepatocytes Can Repopulate Mouse Liver: Histopathology of the Liver in Human Hepatocyte-Transplanted Chimeric Mice and Toxicologic Responses to Acetaminophen

Yasushi Sato1, Hiroshi Yamada1, Kazuhide Iwasaki2, Chise Tateno3, Tsuyoshi Yokoi4, Katsutoshi Yoshizato3,5 and Ikuo Horii1

1 Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Chita-gun, Aichi, Japan
2 Pharmacokinetics Dynamics Metabolism, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Chita-gun, Aichi, Japan
3 Yoshizato Project, Hiroshima Prefectural Institute of Industrial Science and Technology, Cooperative Link of Unique Science and Technology for Economy Revitalization, 1-3-2 Kagamiyama, Higashi-Hiroshima City, Hiroshima, Japan
4 Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
5 Department of Biological Science, Graduate School of Science, Hiroshima, University, 1-3-2 Kagamiyama, Higashi-Hiroshima City, Hiroshima, Japan

Correspondence: Yasushi Sato, Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. 403, Yoshino-cho 1-chome, Kita-ku, Saitama City, Saitama, 331-9530, Japan; e-mail:yasushi.sato{at}po.rd.taisho.co.jp.

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.

Key Words: chimeric mouse • humanized liver • human hepatocytes • bile canaliculi • cytochrome P450 • multidrug resistance protein • acetaminophen

Abbreviations: uPA, urokinase-type plasminogen activator • SCID, severe combined immunodeficiency • APAP, acetaminophen • CK, cytokeratin • hAlb, human albumin • PCNA, proliferating cell nuclear antigen • TUNEL, TdT-dUTP nick end labeling • CYP, cytochrome P450 • MRP, multidrug resistance protein • PGP, P-glycoprotein • PFA, paraformaldehyde • H&E, hematoxylin and eosin • IHC, immunohistochemistry • HRP, horseradish peroxidase • RI, replacement index • CAR, constitutive androstane receptor • NAPQI, N-acetyl-p-benzoquinone imine • HBV, hepatitis B virus • HCV, hepatitis C virus • KO, knockout • TG, transgenic

This version was published on June 1, 2008

Toxicologic Pathology, Vol. 36, No. 4, 581-591 (2008)
DOI: 10.1177/0192623308318212
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