The reconstituted 'humanized liver' in TK-NOG mice is mature and functional.
To overcome the limitations of existing models, we developed a novel experimental in vivo platform for replacing mouse liver with functioning human liver tissue. To do this, a herpes simplex virus type 1 thymidine kinase (HSVtk) transgene was expressed within the liver of highly immunodeficient NOG mice (TK-NOG). Mouse liver cells expressing this transgene were ablated after a brief exposure to a non-toxic dose of ganciclovir (GCV), and transplanted human liver cells are stably maintained within the liver (humanized TK-NOG) without exogenous drug. The reconstituted liver was shown to be a mature and functioning "human organ" that had zonal position-specific enzyme expression and a global gene expression pattern representative of mature human liver; and could generate a human-specific profile of drug metabolism. The 'humanized liver' could be stably maintained in these mice with a high level of synthetic function for a prolonged period (8 months). This novel in vivo system provides an optimized platform for studying human liver physiology, including drug metabolism, toxicology, or liver regeneration.
Biomedical Research Department, Central Institute for Experimental Animals, 1430 Nogawa, Miyamae, Kawasaki, Kanagawa 216-0001, Japan.
Masami
M
Hasegawa
Kenji
K
Kawai
Tetsuya
T
Mitsui
Kenji
K
Taniguchi
Makoto
M
Monnai
Masatoshi
M
Wakui
Mamoru
M
Ito
Makoto
M
Suematsu
Gary
G
Peltz
Masato
M
Nakamura
Hiroshi
H
Suemizu
D000818:Animals; D002352:Carrier Proteins; D015774:Ganciclovir / Q000494:pharmacology; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000502:physiology / Q000637:transplantation; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D013937:Thymidine Kinase / Q000235:genetics; D000099176:Noggin Protein
D002352:Carrier Proteins; D015774:Ganciclovir; D013937:Thymidine Kinase; D000099176:Noggin Protein
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