Severely Immunodeficient TK-NOG mouse

Strain Name	TK-NOG Tg (TK-NOG)

• You will be required to sign a consent form upon purchase.
• The use of this mouse strain corresponds to the use of Living Modified Organism (Cartagene Protocol, domestic law). We will send you an information provision form in advance, so please check it and use it according to the rules of each institution.

Contact form Seminar＆Technical Information

Development

A vector containing an artificial intron and HSVtk gene downstream of the mouse Alb promoter was microinjected into (NOD♀ x NOG♂) F1 mouse pronuclear stage embryos, and the resulting transgenic mouse was backcrossed to NOG mouse.

Product Features

• TK-NOG is a mouse which is HSV-TK (Herpes Simplex Virus-1 Thymidine Kinase) is expressed in the liver under the control of the albumin gene enhancer/promoter, and designed to induce liver-specific damage by ganciclovir administration.
• Transplantation of normal human liver cells via the splenic portal vein into mouse with liver injury reconstitutes the human liver, yielding so-called Hu-liver TK-NOG mouse.

Research Applications

• Hu-Liver TK-NOG mouse production
• Use in the regenerative medicine research, such as transplantation of iPS cell-derived hepatocytes

Humanized Hu-liver TK-NOG mouse

Product features

• In addition to albumin, Hu-liver TK-NOG mouse has been confirmed to synthesize and secrete important serum proteins such as human complement C3, transferrin, and ceruloplasmin.
• Besides, comprehensive gene expression analysis using microarrays showed a high correlation between the gene expression profiles of the transplanted donor hepatocytes and the reconstructed liver, confirming that the characteristics of the donor hepatocytes are reflected in the reconstructed liver.
• It has also been confirmed that drug-metabolizing enzymes are expressed at the same level or higher in the reconstructed liver than in donor hepatocytes.

Products

• Hu-liver TK-NOG mouse chimeric ratio : 70% or more
• Hu-liver TK-NOG mouse chimeric ratio : 40% or more
  Note) The chimeric ratio is calculated from the amount of human albumin in mouse blood.
  Note) Only male is provided.
• You will be required to sign a consent form upon purchase
• The use of this mouse strain corresponds to the use of Living Modified Organism (Cartagene Protocol, domestic law). We will send you an information provision form in advance, so please check it and use it according to the rules of each institution.

Research Applications

• Pharmacokinetic analysis model
• Drug toxicity test model
• Safety test model
• Human disease model (HBV/HCV infection model, liver cancer model)
• Regenerative medicine research model

Phenotypes in Hu-liver TK-NOG mouse

H&E stain

HLA stain

CYP3A4 stain

Glutamine Synthetase stain

We provide chimeric mice in which human liver cells are engrafted

References

2023

The Unique Human N10-Glucuronidated Metabolite Formation from Olanzapine in Chimeric NOG-TKm30 Mice with Humanized Livers. (Olanzapine; NOG-TKm30)
Drug Metab Dispos . 2023 Apr;51(4):480 491. doi: 10.1124/dmd.122.001102. Epub 2023 Jan 9.
Uehara S, Higuchi Y, Yoneda N, Kato H, Yamazaki H, Suemizu H.

Drug transporter expression and activity in cryopreserved human hepatocytes isolated from chimeric TK-NOG mice with humanized livers. (Cell culture; Cell suspension; Drug transporter; Human hepatocytes; Humanized liver mice; Transport activity; TK-NOG mice)
Toxicol In Vitro. 2023 Aug:90:105592. doi: 10.1016/j.tiv.2023.105592. Epub 2023 Apr 7.
Zerdoug A, Le Vée M, Uehara S, Jamin A, Higuchi Y, Yoneda N, Lopez B, Chesné C, Suemizu H, Fardel O.

o-Toluidine metabolism and effects in the urinary bladder of humanized-liver mice.(Bladder; Humanized-liver mice; Liver; Metabolites; o-toluidine; NOG-TKm30)
Toxicology. 2023 Apr:488:153483. doi: 10.1016/j.tox.2023.153483. Epub 2023 Mar 3.
Yokota Y, Suzuki S, Gi M, Yanagiba Y, Yoneda N, Fujioka M, Kakehashi A, Koda S, Suemizu H, Wanibuchi H.

HepaSH cells: Experimental human hepatocytes with lesser inter individual variation and more sustainable availability than primary human hepatocytes.(Chimeric mice; Cytochrome P450; Drugmetabolizing enzyme activity; Experimental human hepatocytes (EHH); HepaSH cells;Humanized liver mouse; Primary human hepatocytes (PHH))
Biochem Biophys Res Commun . 2023 Jun 30:663:132 141. doi: 10.1016/j.bbrc.2023.04.054. Epub 2023 Apr 25.
Shotaro Uehara Yuichiro Higuchi Nao Yoneda Ryoji Ito Takeshi Takahashi Norie Murayama Hiroshi Yamazaki Kazuhiro Murai Hayato Hikita Tetsuo Takehara Hiroshi Suemizu

Roles of human cytochrome P450 3A4/5 in dexamethasone 6β-hydroxylation mediated by liver microsomes and humanized liver in chimeric mice metabolically suppressed with azamulin.(6β-hydroxydexamethasone ; Humanized liver mouse; Time dependent inhibitor)
Drug Metab Pharmacokinet 2023 Jun:50:100504. doi: 10.1016/j.dmpk.2023.100504. Epub 2023 Mar6.
Shotaro Uehara Makiko Shimizu Hiroshi Suemizu Hiroshi Yamazaki

2022

The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. (Hu-Liver TK-NOG)
Biochem Biophys Res Commun . 2011 Feb 18;405(3):405-10. doi: 10.1016/j.bbrc.2011.01.042. Epub 2011 Jan 14.
Masami Hasegawa , Kenji Kawai, Tetsuya Mitsui, Kenji Taniguchi, Makoto Monnai, Masatoshi Wakui, Mamoru Ito, Makoto Suematsu, Gary Peltz, Masato Nakamura, Hiroshi Suemizu

Humanized liver TK-NOG mice with functional deletion of hepatic murine cytochrome P450s as a model for studying human drug metabolism.
Sci Rep. 2022 Sep 1;12(1):14907. doi: 10.1038/s41598-022-19242-0.
H, Ito M, Yamazaki H, Oshimura M, Kazuki Y, Suemizu H.

Cytochrome P450-dependent drug oxidation activities and their expression levels in liver microsomes of chimeric TK-NOG mice with humanized livers.
Drug Metab Pharmacokinet. 2022 Jun;44:100454. doi: 10.1016/j.dmpk.2022.100454. Epub 2022 Feb 25.
Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.

An improved TK-NOG mouse as a novel platform for humanized liver that overcomes limitations in both male and female animals.
Drug Metab Pharmacokinet. 2022 Feb;42:100410. doi:10.1016/j.dmpk.2021.100410. Epub 2021 Jun 12.
Uehara S, Higuchi Y, Yoneda N, Kawai K, Yamamoto M, Kamimura H, Iida Y, Oshimura M, Kazuki Y, Yamazaki H, Hikita H, Takehara T, Suemizu H.

Cytochrome P450s in chimeric mice with humanized liver.
Adv Pharmacol. 2022;95:307-328. doi: 10.1016/bs.apha.2022.05.004. Epub 2022 Jul 23.
Uehara S, Suemizu H, Yamazaki H.

Expression and functional activity of cytochrome P450 enzymes in human hepatocytes with sustainable reproducibility for in vitro phenotyping studies. (Hu-Liver TK-NOG, human hepatocytes)
Adv Pharmacol. 2022;95:285-305. doi: 10.1016/bs.apha.2022.05.009. Epub 2022 Jun 30.
Bachour-El Azzi P, Chesné C, Uehara S.

Formation of reactive metabolites of benzbromarone in humanized-liver mice.
Drug Metab Pharmacokinet. 2022 Aug 5;47:100467. doi: 10.1016/j.dmpk.2022.100467.
Cho N, Suemizu H, Kamimura H, Ohe T, Ito F, Akita H, Kobayashi K.

2021

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice. (HBV, )
J Gastroenterol Hepatol. 2021 Mar;36(3):782-789. doi: 10.1111/jgh.15142. Epub 2020 Jul 7.
Kanbe A, Ishikawa T, Hara A, Suemizu H, Nanizawa E, Tamaki Y, Ito H.

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.
Xenobiotica. 2021 May;51(5):582-589. doi: 10.1080/00498254.2021.1875515. Epub 2021 Feb 18.
Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.

Characterization of plasma protein binding in two mouse models of humanized liver, PXB mouse and humanized TK-NOG mouse.
Xenobiotica. 2021 Jan;51(1):51-60. doi:10.1080/00498254.2020.1808735. Epub 2020 Aug 25.
ki Miyamoto, Yohei Kosugi, Shinji Iwasaki, Ikumi Chisaki, Sayaka Nakagawa, Nobuyuki Amano, Hideki Hirabayashi

In Vivo Functional Analysis of Nonconserved Human lncRNAs Using a Humanized Mouse Model. (TK-NOG, Nonconserved Human lncRNAs )
Methods Mol Biol. 2021;2254:339-347. doi: 10.1007/978-1-0716-1158-6_21.
Ma Y, Jiang CF, Li P, Cao H.

Plasmodium falciparum-infected humanized mice: a viable preclinical tool.
Immunotherapy. 2021 Nov;13(16):1345-1353. doi: 10.2217/imt-2021-0102. Epub 2021 Aug 23.
Tyagi RK.

2020

Human Aldehyde Oxidase 1-Mediated Carbazeran Oxidation in Chimeric TK-NOG Mice Transplanted with Human Hepatocytes.
Drug Metab Dispos. 2020 Jul;48(7):580-586. doi: 10.1124/dmd.120.091090. Epub 2020 May 1.
Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.

Metabolism of desloratadine by chimeric TK-NOG mice transplanted with human hepatocytes.
Xenobiotica . 2020 Jun;50(6):733-740. doi: 10.1080/00498254.2019.1688892. Epub 2019 Nov 12.
Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H.

A long-acting 3TC ProTide nanoformulation suppresses HBV replication in humanized mice. (suppresses HBV replication)
Nanomedicine. 2020 Aug;28:102185. doi: 10.1016/j.nano.2020.102185. Epub 2020 Mar 24.
Wang W, Smith N, Makarov E, Sun Y, Gebhart CL, Ganesan M, Osna NA, Gendelman HE, Edagwa BJ, Poluektova LY.

Attenuated P. falciparum Parasite Shows Cytokine Variations in Humanized Mice.(P. falciparum , TK-NOG, (hRBC-TK-NOG, P. falciparum )
Front Immunol. 2020 Sep 11;11:1801. doi: 10.3389/fimmu.2020.01801. eCollection 2020.
Zhang LL, Li JL, Ji MX, Tian D, Wang LY, Chen C, Tian M.

2019

Predictability of human pharmacokinetics of diisononyl phthalate (DINP) using chimeric mice with humanized liver. (PK/DINP, TK-NOG)
Xenobiotica. 2019 Nov;49(11):1311-1322. doi: 10.1080/00498254.2018.1564087. Epub 2019 Jun 21.
Iwata H, Goto M, Sakai N, Suemizu H, Yamazaki H.

Establishment of the Dual Humanized TK-NOG Mouse Model for HIV-associated Liver Pathogenesis.
J Vis Exp. 2019 Sep 11;(151):10.3791/58645. doi: 10.3791/58645.
Dagur RS, Wang W, Makarov E, Sun Y, Poluektova LY.

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. (DAA; Humanized liver mice; Recombinant HCV; RASs; Hu-Livr TK-NOG).
J Gastroenterol. 2019 May;54(5):449-458. doi: 10.1007/s00535-018-01541-x. Epub 2019 Jan 25.
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.

2018

Humanized Mice Are Instrumental to the Study of Plasmodium falciparum Infection. (TK-NOG, Plasmodium falciparum Infection)
Front Immunol. 2018 Dec 13;9:2550. doi: 10.3389/fimmu.2018.02550. eCollection 2018.
Tyagi RK, Tandel N, Deshpande R, Engelman RW, Patel SD, Tyagi P.

Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.(TK-NOG, metabolic profiles of benzydamine)
Xenobiotica. 2018 Feb;48(2):117-123. doi:10.1080/00498254.2017.1288280. Epub 2017 Feb 21.
Yamazaki-Nishioka M, Shimizu M, Suemizu H, Nishiwaki M, Mitsui M, Yamazaki H.

Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice. (humanized mice, HSC-TK-NOG, HIV)
Biol Open. 2018 Feb 13;7(2):bio029785. doi: 10.1242/bio.029785.
Dagur RS, Wang W, Cheng Y, Makarov E, Ganesan M, Suemizu H, Gebhart CL, Gorantla S, Osna N, Poluektova LY.

2017

Human fetal liver cultures support multiple cell lineages that can engraft immunodeficient mice.(TK-NOG, fetal liver)
Open Biol. 2017 Dec;7(12):170108. doi: 10.1098/rsob.170108.
Fomin ME, Beyer AI, Muench MO.

Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics. (Hu-Liver TK-NOG, DDI)
Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):965-972. doi: 10.1007/s13318-017-0413-2.
Suzuki E, Koyama K, Nakai D, Goda R, Kuga H, Chiba K.

Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.(PBPK modeling, Hu-Liver TK-NOG).
Xenobiotica. 2017 Oct;47(10):844-848. doi: 10.1080/00498254.2016.1247218. Epub 2016 Nov 16.
Shimizu M, Suemizu H, Mitsui M, Shibata N, Guengerich FP, Yamazaki H.

Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling. (Chimeric mouse; MIST guidance; cytochrome P450; disproportionate metabolite; humanized liver; semi-physiological pharmacokinetics. TK-NOG)
Xenobiotica. 2017 May;47(5):382-393. doi:10.1080/00498254.2016.1199063. Epub 2016 Jul 7.
Kamimura H, Ito S, Chijiwa H, Okuzono T, Ishiguro T, Yamamoto Y, Nishinoaki S, Ninomiya SI, Mitsui M, Kalgutkar AS, Yamazaki H, Suemizu H.

Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and Ethanol Metabolism.(JMJD6, HCV/Ethanol Metabolism, Hu-Liver TK-NOG)
Cell Mol Gastroenterol Hepatol. 2017 Oct 16;5(2):101-112. doi: 10.1016/j.jcmgh.2017.10.004. eCollection 2018.
Ganesan M, Tikhanovich I, Vangimalla SS, Dagur RS, Wang W, Poluektova LI, Sun Y, Mercer DF, Tuma D, Weinman SA, Kharbanda KK, Osna NA.

2016

Functional polymer-dependent 3D culture accelerates the differentiation of HepaRG cells into mature hepatocytes. (Hepa-RG, TK-NOG)
Hepatol Res. 2016 Sep;46(10):1045-57. doi: 10.1111/hepr.12644. Epub 2016 Feb 7.
Higuchi Y, Kawai K, Kanaki T, Yamazaki H, Chesné C, Guguen-Guillouzo C, Suemizu H.

Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver. (TK-NOG, HBV)
Sci Rep. 2016 Jun 9;6:27782. doi: 10.1038/srep27782.
Nakabori T, Hikita H, Murai K, Nozaki Y, Kai Y, Makino Y, Saito Y, Tanaka S, Wada H, Eguchi H, Takahashi T, Suemizu H, Sakamori R, Hiramatsu N, Tatsumi T, Takehara T.

Human plasma concentrations of cytochrome P450 probe cocktails extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and from pharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling. (Hepatic clearance; P450 substrates; PBPK modeling, HY-Liver TK-NOG),
Xenobiotica. 2016 Dec;46(12):1049-1055. doi: 10.3109/00498254.2016.1147102. Epub 2016 Feb 25.
Utoh M, Suemizu H, Mitsui M, Kawano M, Toda A, Uehara S, Uno Y, Shimizu M, Sasaki E, Yamazaki H.

2015

Humanized thymidine kinase-NOG mice can be used to identify drugs that cause animal-specific hepatotoxicity: a case study with furosemide.
J Pharmacol Exp Ther . 2015 Jul;354(1):73-8. doi: 10.1124/jpet.115.224493. Epub 2015 May 11.
Xu D, Michie SA, Zheng M, Takeda S, Wu M, Peltz G.

Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice.
J Virol. 2015 Oct;89(19):10087-96. doi: 10.1128/JVI.01126-15. Epub 2015 Aug 5.
Uchida T, Hiraga N, Imamura M, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Yoshizato K, Ohdan H, Murakami K, Chayama K.

Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.
J Pharmacol Exp Ther. 2015 Feb;352(2):274-80. doi: 10.1124/jpet.114.220798. Epub 2014 Nov 25.
Takeda ST, Guan Y, Guo Y, Peltz G.

Formation of the accumulative human metabolite and human-specific glutathione conjugate of diclofenac in TK-NOG chimeric mice with humanized livers.
Drug Metab Dispos. 2015 Mar;43(3):309-16. doi: 10.1124/dmd.114.061689. Epub 2014 Dec 11.
Kamimura H, Ito S, Nozawa K, Nakamura S, Chijiwa H, Nagatsuka S, Kuronuma M, Ohnishi Y, Suemizu H, Ninomiya S.

Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice. (TK-NOG, Plasmodium falciparum full life cycle ),
Nat Commun. 2015 Jul 24;6:7690. doi: 10.1038/ncomms8690.
Soulard V, Bosson-Vanga H, Lorthiois A, Roucher C, Franetich JF, Zanghi G, Bordessoulles M, Tefit M, Thellier M, Morosan S, Le Naour G, Capron F, Suemizu H, Snounou G, Moreno-Sabater A, Mazier D.

Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice. (HCV infection, HU-Liver TK-NOG, (Asunaprevir/daclatasvir; Ledipasvir/sofosbuvir; Resistance-associated variants (RAVs)).
J Gastroenterol. 2015 Nov;50(11):1145-51. doi: 10.1007/s00535-015-1108-6. Epub 2015 Jul 25.
Kai Y, Hikita H, Tatsumi T, Nakabori T, Saito Y, Morishita N, Tanaka S, Nawa T, Oze T, Sakamori R, Yakushijin T, Hiramatsu N, Suemizu H, Takehara T.