Department of Applied Research for Laboratory Animals

Liver Engineering Laboratory

Liver Engineering Laboratory has been creating a new humanized animal model by modification of NOG mice, especially focusing on development of a liver-humanized model. We established TK-NOG strain which is a drug-induced liver failure model. The expression unit of herpes simplex virus thymidine kinase was introduced to NOG mouse by using microinjection technique. The TK-NOG mice can bear human hepatocytes at high rates on the basis of extremely high acceptability of xenogeneic cells. We succeeded to replace the mouse liver nearly 80% with human hepatocytes. The "humanized liver" reconstructed with human hepatocytes has been shown to have drug metabolizing properties similar to those of the human liver. In addition, we further improve the NOG mouse by using a microsatellite marker assisted selection protocol (known as speed congenic) to efficiently replace the genetic background of conventional transgenic mouse and knockout mouse to that of NOG strain (super immunnodeficient) while preserving the characteristics.

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※Reference
  1. Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes.
    Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.
    Xenobiotica. 2021 May;51(5):582-589.
  2. Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.
    Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, Takehara T.
    Gastroenterology. 2021 Apr;160(5):1741-1754.e16.
  3. Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential.
    Miura T, Shimizu M, Uehara S, Yoshizawa M, Nakano A, Yanagi M, Kamiya Y, Murayama N, Suemizu H, Yamazaki H.
    Chem Res Toxicol. 2020 Dec 21;33(12):3048-3053.
  4. Comparative Transcriptomics Analyses in Livers of Mice, Humans, and Humanized Mice Define Human-Specific Gene Networks.
    Jiang C, Li P, Ruan X, Ma Y, Kawai K, Suemizu H, Cao H.
    Cells. 2020 Nov 30;9(12):2566.
  5. Metabolic Profiles of Tetrabromobisphenol A in Humans Extrapolated from Humanized-Liver Mouse Data Using a Simplified Physiologically Based Pharmacokinetic Model.
    Miura T, Uehara S, Shigeta K, Yoshizawa M, Kamiya Y, Murayama N, Shimizu M, Suemizu H, Yamazaki H.
    Chem Res Toxicol. 2021 Feb 15;34(2):522-528.
  6. Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis.
    Ruan X, Li P, Ma Y, Jiang CF, Chen Y, Shi Y, Gupta N, Seifuddin F, Pirooznia M, Ohnishi Y, Yoneda N, Nishiwaki M, Dumbovic G, Rinn JL, Higuchi Y, Kawai K, Suemizu H, Cao H.
    J Clin Invest. 2021 Jan 4;131(1):e136336.
  7. Human Aldehyde Oxidase 1-Mediated Carbazeran Oxidation in Chimeric TK-NOG Mice Transplanted with Human Hepatocytes.
    Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.
    Drug Metab Dispos. 2020 Jul;48(7):580-586.
  8. Hepatitis C virus infection suppresses hepatitis B virus replication via the RIG-I-like helicase pathway.
    Murai K, Hikita H, Kai Y, Kondo Y, Fukuoka M, Fukutomi K, Doi A, Yamai T, Nakabori T, Fukuda R, Takahashi T, Miyakawa K, Suemizu H, Ryo A, Yamada R, Kodama T, Sakamori R, Tatsumi T, Takehara T.
    Sci Rep. 2020 Jan 22;10(1):941.
  9. Expansion, in vivo-ex vivo cycling, and genetic manipulation of primary human hepatocytes.
    Michailidis E, Vercauteren K, Mancio-Silva L, Andrus L, Jahan C, Ricardo-Lax I, Zou C, Kabbani M, Park P, Quirk C, Pyrgaki C, Razooky B, Verhoye L, Zoluthkin I, Lu WY, Forbes SJ, Chiriboga L, Theise ND, Herzog RW, Suemizu H, Schneider WM, Shlomai A, Meuleman P, Bhatia SN, Rice CM, de Jong YP.
    Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1678-1688.
  10. In vivo functional analysis of non-conserved human lncRNAs associated with cardiometabolic traits.
    Ruan X, Li P, Chen Y, Shi Y, Pirooznia M, Seifuddin F, Suemizu H, Ohnishi Y, Yoneda N, Nishiwaki M, Shepherdson J, Suresh A, Singh K, Ma Y, Jiang CF, Cao H.
    Nat Commun. 2020 Jan 2;11(1):45.
  11. Combinations of two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents are effective for hepatitis C virus with NS5A-P32 deletion in humanized-liver mice.
    Doi A, Hikita H, Kai Y, Tahata Y, Saito Y, Nakabori T, Yamada R, Kodama T, Sakamori R, Murayama A, Nitta S, Asahina Y, Suemizu H, Tatsumi T, Kato T, Takehara T.
    J Gastroenterol. 2019 May;54(5):449-458.
  12. Expression and inducibility of cytochrome P450s in human hepatocytes isolated from chimeric mice with humanised livers.
    Uehara S, Higuchi Y, Yoneda N, Yamazaki H, Suemizu H.
    Xenobiotica. 2019 Jun;49(6):678-687.
  13. Chimeric mice with humanized liver as a model for testing organophosphate and carbamate pesticide exposure.
    Suemizu H, Kawai K, Murayama N, Nakamura M, Yamazaki H.
    Pest Manag Sci. 2018 Jun;74(6):1424-1430.

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