The reconstituted 'humanized liver' in TK-NOG mice is mature and functional

Masami Hasegawa, Kenji Kawai, Tetsuya Mitsui, Kenji Taniguchi, Makoto Monnai, Masatoshi Wakui, Mamoru Ito, Makoto Suematsu, Gary Peltz, Masato Nakamura, Hiroshi Suemizu

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)405-410
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume405
Issue number3
DOIs
Publication statusPublished - 2011 Feb 18

Fingerprint

Liver
Transgenes
Metabolism
Pharmaceutical Preparations
Ganciclovir
Liver Regeneration
Thymidine Kinase
Human Herpesvirus 1
Physiology
Toxicology
Viruses
Gene expression
Cells
Gene Expression
Tissue
Enzymes

Keywords

  • Drug metabolism
  • Herpes simplex virus type 1 thymidine kinase (HSVtk)
  • Humanized mouse
  • Liver reconstitution

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. / Hasegawa, Masami; Kawai, Kenji; Mitsui, Tetsuya; Taniguchi, Kenji; Monnai, Makoto; Wakui, Masatoshi; Ito, Mamoru; Suematsu, Makoto; Peltz, Gary; Nakamura, Masato; Suemizu, Hiroshi.

In: Biochemical and Biophysical Research Communications, Vol. 405, No. 3, 18.02.2011, p. 405-410.

Research output: Contribution to journalArticle

Hasegawa, M, Kawai, K, Mitsui, T, Taniguchi, K, Monnai, M, Wakui, M, Ito, M, Suematsu, M, Peltz, G, Nakamura, M & Suemizu, H 2011, 'The reconstituted 'humanized liver' in TK-NOG mice is mature and functional', Biochemical and Biophysical Research Communications, vol. 405, no. 3, pp. 405-410. https://doi.org/10.1016/j.bbrc.2011.01.042
Hasegawa, Masami ; Kawai, Kenji ; Mitsui, Tetsuya ; Taniguchi, Kenji ; Monnai, Makoto ; Wakui, Masatoshi ; Ito, Mamoru ; Suematsu, Makoto ; Peltz, Gary ; Nakamura, Masato ; Suemizu, Hiroshi. / The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. In: Biochemical and Biophysical Research Communications. 2011 ; Vol. 405, No. 3. pp. 405-410.
@article{14f52385a35040b0b29bd23c5974d023,
title = "The reconstituted 'humanized liver' in TK-NOG mice is mature and functional",
abstract = "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.",
keywords = "Drug metabolism, Herpes simplex virus type 1 thymidine kinase (HSVtk), Humanized mouse, Liver reconstitution",
author = "Masami Hasegawa and Kenji Kawai and Tetsuya Mitsui and Kenji Taniguchi and Makoto Monnai and Masatoshi Wakui and Mamoru Ito and Makoto Suematsu and Gary Peltz and Masato Nakamura and Hiroshi Suemizu",
year = "2011",
month = "2",
day = "18",
doi = "10.1016/j.bbrc.2011.01.042",
language = "English",
volume = "405",
pages = "405--410",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",

}

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

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

UR - http://www.scopus.com/inward/record.url?scp=79951576827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951576827&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2011.01.042

DO - 10.1016/j.bbrc.2011.01.042

M3 - Article

VL - 405

SP - 405

EP - 410

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -