Phoenixbio Co., Ltd.

Hiroshima Industrial Promotion Organization

Tokyo Metropolitan Institute of Medical Science

Chugai Seiyaku Kabushiki Kaisha

Japan Science and Technology Agency

Riken Corporation

Hiroshima University

Tottori University

Biointegrence Inc.

National University Corporation Tottori University

Chise Mukaidani

Katsutoshi Yoshizato

Michinori Kohara

Satoko Hamamura

Koichi Jishage

Yosuke Kawase

Miho Kataoka

Hiroki Oshita

Masakazu Kakuni

Mitsuo Oshimura

Kota Kato

Yasuhiro Kazuki

Takashi Shimada

Norio Masumoto

Fuyuki Miya

Chihiro Yamasaki

Hidetaka Kamimura

Tatsuhiko Tsunoda

Akio Kawamura

Yumiko Iwasaki

Naoyuki Nakada

Masaaki Arai

Masato Ohbuchi

Fuyuki c/o Riken Miya

Tatsuhiko c/o Riken Tsunoda

Mibo Kataoka

The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of:

Urokinase-type plasminogen activator transgenic mouse

Provided is a non-human animal that is highly practical as a hyperuricenia model, the non-human animal being the following:

Mouse model of hyperuricemia

The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

A chimeric non-human animal having an in vivo human hepatocyte population, wherein the effects of non-human animal cells on drug metabolism are suppressed or deleted is provided. A method for producing a chimeric non-human animal that lacks a drug-metabolizing system or has a suppressed drug-metabolizing system and is provided with a drug-metabolizing system driven by human hepatocytes, is provided. The method comprises transplanting human hepatocytes into a non-human animal characterized by (i) being immunodeficient, (ii) having liver damage, and (iii) lacking the functions of an endogenous Cyp3a gene.

Chimeric non-human animal carrying human hepatocyte

A polynucleotide encoding the amino acid shown in SEQ ID NO:2 or SEQ ID NO: 5, or encoding an amino acid sequence having not less than 98% identity thereto; preferably a polynucleotide comprising replacement of the amino acid corresponding to glutamic acid at position 1202 of SEQ ID NO:2 (position 177 of SEQ ID NO:5) with glycine, replacement of the amino acid corresponding to glutamic acid at position 1056 (position 31 of SEQ ID NO:5) with valine, and replacement of the amino acid corresponding to alanine at position 2199 (position 1174 of SEQ ID NO:5) with threonine.

Polynucleotide derived from novel hepatitis C virus strain and use thereof

Disclosed is a nonhuman animal showing the symptoms of human nonalcoholic steatohepatitis which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal and then transplanting human hepatocytes that are propagated in the body of the chimeric nonhuman animal into an immunodeficient hepatopathic nonhuman animal of the same species as the immunodeficient hepatopathic nonhuman animal described above, as well as a nonhuman animal showing the symptoms of human fatty liver which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal.

Nonalcoholic steatohepatitis model rodent and fatty liver model rodent

Human adult hepatocytes are transplanted into an immunodeficient hepatopathy mouse and then human growth hormone is administered to the mouse to thereby elevate twice or more the replacement ratio by the human adult hepatocytes having been transplanted. Further, human growth hormone is administered to an immunodeficient hepatopathy mouse carrying human young hepatocytes transplanted thereinto so as to improve fatty liver of the mouse in which about 70% or more of the hepatocytes have been replaced by the human hepatocytes.

Method of treating mouse carrying human hepatocytes

Transplanting human hepatocytes into a liver of an immunodeficient hepatopathy mouse, and then feeding the mouse transplanted with the human hepatocytes under such a condition as being protected from the attack by human complement produced by the human hepatocytes thereby proliferating the transplanted human hepatocytes in the mouse liver. Further, obtaining human hepatocytes in large scale by repeating the above steps using the proliferated human hepatocytes.

Method of proliferating human hepatocytes and method for obtaining human hepatocytes

The invention provides a monoclonal antibody which specifically recognizes proliferative human hepatocytes, a method for isolating proliferative human hepatocytes by using the antibody, and a method for inducing to differentiate the proliferative human hepatocytes to functional human hepatocytes. Further, the invention provides the proliferative human hepatocytes and functional human hepatocytes obtained by the methods, as well as a cell kit and a hybrid artificial liver comprising those hepatocytes.

Antibody recognizing proliferative human liver cells, proliferative human liver cells and functional human liver cells

Growing community of inventors

Higashihiroshima, Japan

Chise Mukaidani