TY - JOUR
T1 - The reconstituted 'humanized liver' in TK-NOG mice is mature and functional
AU - Hasegawa, Masami
AU - Kawai, Kenji
AU - Mitsui, Tetsuya
AU - Taniguchi, Kenji
AU - Monnai, Makoto
AU - Wakui, Masatoshi
AU - Ito, Mamoru
AU - Suematsu, Makoto
AU - Peltz, Gary
AU - Nakamura, Masato
AU - Suemizu, Hiroshi
N1 - Funding Information:
We thank Dr. R.D. Palmiter for providing the plasmid p2335A-1 containing the mouse albumin enhancer/promoter gene, and M. Kuronuma, S. Inoue, Y. Ando, N. Ogata, T. Mizushima, E. Hayakawa, K. Hioki, T. Sugioka, T. Ogura, T. Kamisako, and T. Etoh for outstanding technical assistance with the animal experiments. We thank C. Yagihashi and N. Omi for technical assistance with molecular analyses, and Drs. M. Kajimura, M. Ohmura, and Y. Ohnishi for helpful discussions. This work was supported by a Grant-in-Aid for Scientific Research ( 17300136 and 21240042 ) to H.S. Design of metabolome analysis in humanized NOG mice was supported by Research and Development of the Next-Generation Integrated Simulation of Living Matter, a part of the Development and Use of the Next-Generation Supercomputer Project of MEXT. M.S. is supported by JST, ERATO, Suematsu Gas Biology Project, Tokyo 160-8582, Japan. G.P. was supported by funding from a transformative RO1 award (1R01DK090992-01) from the NIDDK.
PY - 2011/2/18
Y1 - 2011/2/18
N2 - 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.
AB - 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.
KW - Drug metabolism
KW - Herpes simplex virus type 1 thymidine kinase (HSVtk)
KW - Humanized mouse
KW - Liver reconstitution
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U2 - 10.1016/j.bbrc.2011.01.042
DO - 10.1016/j.bbrc.2011.01.042
M3 - Article
C2 - 21238430
AN - SCOPUS:79951576827
SN - 0006-291X
VL - 405
SP - 405
EP - 410
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -