Toxicologic Pathology

 

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First published on May 8, 2008, doi:10.1177/0192623308318212

Toxicologic Pathology 2008;36:581.

A more recent version of this article appeared on June 1, 2008

Article

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

Yasushi Sato*, Hiroshi Yamada, Kazuhide Iwasaki, Chise Tateno, Tsuyoshi Yokoi, Katsutoshi Yoshizato, and Ikuo Horii

* To whom correspondence should be addressed. E-mail: Yasushi.Sato{at}pfizer.com.


  Abstract
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.


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