Construction of in vitro liver model using ES, iPS, or somatic stem cells, and its application for drug metabolism assay

2011 Fiscal Year Final Research Report

• Project/Area Number: 21300178
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biomedical engineering/Biological material science
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: TAGAWA Yoh-ichi 東京工業大学, 大学院・生命理工学研究科, 准教授 (70262079)
• Co-Investigator(Renkei-kenkyūsha): OZEKI Eiichi 株式会社島津製作所, 主幹研究員 (30192529) ; MIYAGAWA Shinichi 信州大学, 医学部, 教授 (80229806)
• Project Period (FY): 2009 – 2011
• Keywords: バイオチップ / 肝 / 薬物代謝 / 毒性試験 / ES細胞

Research Abstract

We have succeeded to establish to construct in vitro liver model culturing primary hepatocytes, portal vein-ligation-induced hepatic stem cells, or human ES/iPS cell-derived hepatocytes with the networks of endothelial cells on EHS gels. The culture of these in vitro liver models in our original microfluidic system had significantly larger advantages for liver specific potentials compared to the non-fluidic. Our results lead strong expectation of our in vitro liver chips for application of drug metabolism and disposition.

Research Products

• [Journal Article] Acetoaminophen-induced hepatotoxicity in a liver tissue model consisting of primary hepatocytes assembling around an endothelial cell network (2011)
  • Author(s): Toyoda, Y., M. Tamai, K. Kashikura, S. Kobayashi, Y. Fujiyama, T. Soga, and Y. Tagawa^*
  • Journal Title: Drug Metab. Dispos Volume: 40 Pages: 169-177
• [Journal Article] Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy (2011)
  • Author(s): Hayashi, T, A. Horiuchi, K. Sano, N. Hiraoka, M. Kasai, T. Ichimura, T. Sudo, Y. Tagawa, R. Nishimura, Ol Ishiko, Y. Kanai, N. Yaegashi, H. Aburatani, T. Shiozawa, I. Konishi
  • Journal Title: Sci. Rep. Volume: 1 Pages: 180
• [Journal Article] Mitochondrial development of the in vitro he patic organogenesis model with simultaneous cardiac mesoderm differentiation from murine induced pluripotent stem cells (2011)
  • Author(s): Tamai, M., A, Yamashita, and Y. Tagawa
  • Journal Title: J. Biosci. Bioeng Volume: 122 Pages: 495-500
• [Journal Article] Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor (2011)
  • Author(s): Denda, K., K. Nkano-Wakabayashi, N. Okamoto, N. Kitamura, J. Ryu, Y. Tagawa, T. Ichisaka, S. Yamanaka, and M. Komada
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 28802-28810
• [Journal Article] Expression of human factors CD81, claudin-1, scavenger receptor, and occluding in mouse hepatocytes does not confer susceptibility to HCV entry (2011)
  • Author(s): Hikosaka, K., H. Noritake, W. Kimura, N. Sultana, M. T. K. Sharkar, Y. Tagawa, T. Uezato, Y. Kobayashi, T. Wakita, and N. Miura
  • Journal Title: Biomedical Research Volume: 32 Pages: 143-150
• [Journal Article] 肝機能デバイスの開発 (2010)
  • Author(s): 明地将一、藤山陽一、玉井美保、田川陽一
  • Journal Title: 島津評論 Volume: 67 Pages: 53-59
• [Journal Article] Direct ex vivo expansion of hematopoietic stem cells from umbilical cord blood on membranes (2010)
  • Author(s): A. Higuchi, S.-T. Yang, P.-T. Li, M. Tamai, Y. Tagawa, Y. Chang, Y. Chang, Q.-D. Ling, S.-T. Hsu
  • Journal Title: J. Membrane Science Volume: 351 Pages: 104-111
• [Journal Article] Polymeric Membranes for Chiral Separation of Pharmaceuticals and Chemicals-Short title ; Membranes for Chiral Separation (2010)
  • Author(s): A. Higuchi, M. Tamai, Y.-A. Ko, Y. Tagawa Y-H Wu, B. D. Freeman, J.-T. Bing, Y. Chang, Q.-D. Ling
  • Journal Title: Polymer Reviews Volume: 50 Pages: 113-143
• [Journal Article] Characterization of a variant virus from ascites of subacute granulomatous serositis in interferon-γ-deficient C57BL/6 mice persistently infected with murine coronavirus (2010)
  • Author(s): Kyuwa, S., S. Takagaki, S. Matsuyama, F. Taguchi, J. Saegusa, Y. Iwakura, Y. Tagawa, and Y. Yoshikawa
  • Journal Title: strain JHM. Viral Immunology Volume: 23 Pages: 437-442
• [Journal Article] Carbonate apatite-facilitated intracellulary delivered siRNA for efficient knockdown of functional genes (2010)
  • Author(s): Hossain, S., A. Stanislaus, MJ, Chua, S. Tada, Y. Tagawa, EH. Chowdhury, T. Akaike
  • Journal Title: J. Control. Release Volume: 147 Pages: 101-108
• [Journal Article] Isolation and characterization of portal branch ligation-stimulated Hmga2-positive bipontent hepatic progenitor cells (2010)
  • Author(s): Sakai, H., Y. Tagawa, M. Tamai, H. Motoyama, S. Ogawa, J. Soeda, T. Nakata, S. Miyagawa
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 403 Pages: 298-304
• [Journal Article] Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver (2010)
  • Author(s): Iinuma, N., T. Sakurai, A. Kamiyoshi, Y. Ichikwawa-Shindo, T. Arai, T. Yoshizawa, T. Koyama, R. Uetake, H. Kawate, S. Muto, Y. Tagawa, S. Miyagawa, T. Shindo
  • Journal Title: Peptides Volume: 31 Pages: 865-871
• [Journal Article] In vitro reprogramming of adult hepatoc ytes into insulin-producing cells without viral vectors (2009)
  • Author(s): Motoyama, H., Ogawa, S., Kubo, A., Miwa, S., Nakayama, J., Tagawa, Y., and Miyagawa, S.
  • Journal Title: Biochem. Biophys. Res. Commun. 3 Volume: 85 Pages: 123-128
• [Journal Article] IFN-γdeficiency worsen Pneumocystis pneumonia with Th17 development in nude mice (2009)
  • Author(s): Hu, T., Takamoto, M., Hida S., Tagawa, Y., and Sugane, K.
  • Journal Title: Immunol Lett. Volume: 127 Pages: 55-59
• [Presentation] マウス個体を用いたアセトアミノフェン誘導肝障害モデル構築の試み:概日リズムと肝毒性との相関性 (2011)
  • Author(s): 守矢恒司、豊田優、田川陽一
  • Organizer: 日本分子生物学会(第34回日本分子生物学会年会)
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] Clonality of pancreatic acini and ducts in chimeric mice (2011)
  • Author(s): Je-young Ryu and Yoh-ichi Tagawa
  • Organizer: 日本分子生物学会(第34回日本分子生物学会年会)
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] ヒトES/iPS細胞を用いたin vitroヒト肝組織モデルの構築 (2011)
  • Author(s): 安成晧,三田村圭祐,安達栄治郎,田川陽一
  • Organizer: 日本分子生物学会(第34回日本分子生物学会年会)
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] オッセオインテグレーションにおける線維芽細胞の影響 (2011)
  • Author(s): 張本乾一,長岡紀幸,鈴木一臣,吉田靖弘,田川陽一
  • Organizer: 第33回日本バイオマテリアル学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-11-21
• [Presentation] Development and validation of in vitro liver tissue model consisting of primary hepatocytes assembling around an endothelial network (2011)
  • Author(s): Yu Toyoda, Miho Tamai, Koji Moriya, Shunsuke Kobayashi and Yoh-ichi Tagawa
  • Organizer: 6th Toin international symposium on Biomedical engineering 2011
  • Place of Presentation: 横浜
  • Year and Date: 2011-11-05
• [Presentation] Mouse model for acetaminophen-induced liver injury for screening of hepatoprotective compounds (2011)
  • Author(s): Koji Moriya, Yu Toyoda, Yoh-ichi Tagawa
  • Organizer: 6th Toin international symposium on Biomedical engineering 2011
  • Place of Presentation: 横浜
  • Year and Date: 2011-11-05
• [Presentation] Advantage of Osteoblasts in Cell Competition on Biomaterials (2011)
  • Author(s): Kenichi Harimoto, Noriyuki Nagaoka, Kazuomi Suzuki, Yasuhiro Yoshida, & Yoh-ichi Tagawa
  • Organizer: 6th Toin international symposium on Biomedical engineering 2011
  • Place of Presentation: 横浜
  • Year and Date: 2011-11-05
• [Presentation] Development of pancreatic acinar cells in chimera of eGFP and DsRed2 (2011)
  • Author(s): Je-young Ryu and Yoh-ichi Tagawa
  • Organizer: 6th Toin international symposium on Biomedical engineering 2011
  • Place of Presentation: 横浜
  • Year and Date: 2011-11-05
• [Presentation] In vitro model of liver organogenesis using embryonic stem cells (2011)
  • Author(s): Yoh-ichi Tagawa
  • Organizer: Taiwanese Society of Molecular Medicine
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2011-11-02
• [Presentation] 合成生物学による肝組織モデルの構築を目指して (2011)
  • Author(s): 田川陽一,安成晧,玉井美保
  • Organizer: 日本生物工学会(第63回大会)
  • Place of Presentation: 東京
  • Year and Date: 2011-09-27
• [Presentation] Acetaminophen-induced hepatotoxicity in liver tissue-like structure consisting of primary hepatocytes assembling around endothelial cell network (2011)
  • Author(s): Yu Toyoda, Koji Moriya, Shunsuke Kobayashi, Miho Tamai, Eijiro Adachi, and Yoh-ichi Tagawa
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] Acetaminophen-induced hepatotoxicity in a liver tissue model consisting of primary hepatocytes assembling around an endothelial cell network (2011)
  • Author(s): Yu Toyoda, Koji Moriya and Yoh-ichi Tagawa
  • Organizer: 2011 International Graduate Forum on Biotechnology, Bioengineering and Biomedical Science(IGF3B-2011)
  • Place of Presentation: Beijing, China
  • Year and Date: 2011-08-27
• [Presentation] Advantage of Osteoblasts in Cell Competition on Biomaterials (2011)
  • Author(s): Kenichi Harimoto, Noriyuki Nagaoka, Kazuomi Suzuki, Yasuhiro Yoshida, & Yoh-ichi Tagawa
  • Organizer: 2011 International Graduate Forum on Biotechnology, Bioengineering and Biomedical Science(IGF3B-2011)
  • Place of Presentation: Beijing, China
  • Year and Date: 2011-08-27
• [Presentation] Dynamics of Metal Ions in Murine Embryonic Stem Cells (2011)
  • Author(s): Hiroaki Aikawa, Yoh-ichi Tagawa, Tadashi Saito, Yuko Fujiwara, Yuki Mizobuchi, and Masaya Kawase
  • Organizer: 2011 International Graduate Forum on Biotechnology, Bioengineering and Biomedical Science(IGF3B-2011)
  • Place of Presentation: Beijing, China
  • Year and Date: 2011-08-27
• [Presentation] In vivo organization of vascularized hepatic tissues model with fibroblast-embedded collagen fibrils formation at intraperitoneal sites in partially hepatectomised mice (2011)
  • Author(s): Miho Tamai, Toshihiro Akaike, Eijiro Adachi, Yoh-ichi Tagawa
  • Organizer: Gordon Research Conference on collagen
  • Place of Presentation: New London, USA
  • Year and Date: 2011-07-22
• [Presentation] 細胞組織工学を応用した肝毒性評価系の開発 (2011)
  • Author(s): 豊田優,守矢恒司,山下晃平,小林俊介,田川陽一
  • Organizer: 第18回肝細胞研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-24
• [Presentation] ヒトiPS細胞を用いたヒト型肝組織のin vitro構築 (2011)
  • Author(s): 安成晧、田川陽一
  • Organizer: 第10回日本再生医療学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-03-01
• [Presentation] 細胞組織工学を応用したex vivo肝毒性評価系の開発 (2010)
  • Author(s): 豊田優、守矢恒司、玉井美保、山下晃平、赤池敏宏、安達栄次郎、田川陽一
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] バイオマテリアルに対する細胞の接着性がオッセオインテグレーションに及ぼす影響 (2010)
  • Author(s): 張本乾一,長岡紀幸,赤池敏宏,鈴木一臣,吉田靖弘,田川陽一
  • Organizer: 第32回日本バイオマテリアル学会大会
  • Place of Presentation: 広島
  • Year and Date: 2010-11-29
• [Presentation] 増殖性肝前駆様細胞を用いた高密度コラーゲンゲルによる3次元肝組織化 (2010)
  • Author(s): 玉井美保、酒井宏司、宮川眞一、赤池敏宏、安達栄次郎、田川陽一
  • Organizer: 第32回日本バイオマテリアル学会大
  • Place of Presentation: 広島
  • Year and Date: 2010-11-29
• [Presentation] In vitro systems of liver organogenesis derived from murineorhuman iPS cell have high multiple hepatic potentials in long culture (2010)
  • Author(s): Yoh-ichi Tagawa
  • Organizer: International Conference on Systems Biology of Stem Cell
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2010-10-17
• [Presentation] Cell-adhesive advantage of osteoblasts on titanium in the model of in vitro osseointegration (2010)
  • Author(s): K. Harimoto, N. Nagaoka, T. Akaike, K. Suzuki, Y. Yoshida, Y. Tagawa
  • Organizer: 2010 Tissue Engineering and Regenerative Medicine International Symposium-Asia & Pacific
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2010-09-15
• [Presentation] High hepatic potentials in liver tissue micro-sized flow-culture system using murine or human ES/iPS cell (2010)
  • Author(s): Yoh-ichi Tagawa
  • Organizer: 2010 Tissue Engineering and Regenerative Medicine International Symposium-Asia & Pacific
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2010-09-15
• [Presentation] In vitro systems of liver organogenesis derived from murine or human iPS cell have high multiple hepatic potentials in long culture (2010)
  • Author(s): S. Ahn, A. Yamashita, M. Tamai, T. Akaike, and Y. Tagawa
  • Organizer: International Society for Stem Cell Research, 8th Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2010-06-16
• [Presentation] バイオマテリアルに対する細胞の接着性が骨形成に及ぼす影響 (2010)
  • Author(s): 張本乾一,長岡紀幸,赤池敏宏,鈴木一臣,吉田靖弘,田川陽一
  • Organizer: 第9回日本再生医療学会総会
  • Place of Presentation: 広島
  • Year and Date: 2010-03-18
• [Presentation] 門脈結紮による肝前駆細胞の増殖誘導 (2010)
  • Author(s): 酒井宏司、玉井美保、奥山久嗣、本山博章、小川真一郎、田川陽一、宮川眞一
  • Organizer: 第9回日本再生医療学会総会
  • Place of Presentation: 広島
  • Year and Date: 2010-03-18
• [Presentation] 肝様組織チップを用いたex vivo肝毒性評価系の構築 (2009)
  • Author(s): 豊田優、玉井美保、奥山久嗣、小林俊介、新藤隆行、安達栄治郎、藤山陽一、小関英一、田川陽一
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-09
• [Presentation] Developmental Engineering and Development of Novel Artificial Liver System (2009)
  • Author(s): Y. Tagawa
  • Organizer: Seminar at National Cheng Kung University
  • Place of Presentation: Tainan, Taiwan
  • Year and Date: 2009-12-04
• [Presentation] ES細胞等を用いた肝組織チップの開発 (2009)
  • Author(s): 安成晧、玉井美保、豊田優、奥山久嗣、赤池敏宏、新藤隆行、藤山陽一、小関英一、田川陽一
  • Organizer: 第22回日本動物実験代替法学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-14
• [Presentation] Hepatic Portal Branch Ligation-Stimulated Appearance of Bipotent Hepatic Progenitor Cells in Mice (2009)
  • Author(s): Hiroshi Sakai, Yoh-ichi Tagawa, Hiroaki Motoyama, Shinichiro Ogawa, Shinichi Miyagawa
  • Organizer: 2009 Meeting of the International Society for Stem Cell Research(ISSCR)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2009-11-08
• [Presentation] Developmental Engineering and Development of Novel Artificial Liver System (2009)
  • Author(s): Y. Tagawa
  • Organizer: 2009 Asia Conference for Biomaterials & Stem cell Techniques in Dong Hwa University
  • Place of Presentation: Hualien, Taiwan
  • Year and Date: 2009-09-22
• [Presentation] Developmental Analysis using Multi-Color Fluorescent Embryonic Stem Cell Lines (2009)
  • Author(s): Y. Tagawa
  • Organizer: 2009 Asia Conference for Biomaterials & Stem Cell Techniques
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2009-09-10
• [Presentation] New Role of Feeder Cells to Embryonic Stem Cells-Metal Analysis of Embryonic Stem Cells by ICP-MS (2009)
  • Author(s): Hiroaki Aikawa, Tadashi Saito, Yuko Fujiwara, Yuki Mizobuchi, Toshihiro Akaike, Yoh-ichi Tagawa, Masaya Kawase
  • Organizer: 2nd World Congress of the Tissue Engineering and Regenerative Medicine International Society(TERMIS) in conjunction with 2009 Seoul Stem Cell Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-08-31
• [Presentation] Establishment of the High Density Culturing System Using Primary Culture of Hepatocyte (2009)
  • Author(s): Miho TAMAI, Satoshi HOSOYA, Toshihiro AKAIKE, Eijiro ADACHI, Yoh-ichi TAGAWA
  • Organizer: 2nd World Congress of the Tissue Engineering and Regenerative Medicine International Society(TERMIS) in conjunction with 2009 Seoul Stem Cell Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-08-31
• [Presentation] 初代培養肝細胞を用いた再構成コラーゲンゲル内培養の検討 (2009)
  • Author(s): 玉井美保、細谷智、赤池敏宏、安達栄次郎、田川陽一
  • Organizer: 第16回肝細胞研究会
  • Place of Presentation: 山形
  • Year and Date: 2009-06-26
• [Book] 実験医学別冊核酸実験の原理とプロトコール(平尾一郎、胡桃坂仁志編集) (2011)
  • Author(s): 三田村圭祐、田川陽一
  • Total Pages: 167-180
  • Publisher: 羊土社
• [Book] IFN「seriesモデル動物利用マニュアル疾患モデルの作製と利用免疫疾患」(岩倉洋一郎監修) (2011)
  • Author(s): 瀧伸介、田川陽一
  • Total Pages: 361-367
  • Publisher: エル・アイ・シー
• [Book] バイオ研究のフロンティア医療・診断をめざす先端バイオロジー (2009)
  • Author(s): 田川陽一, 他
  • Total Pages: 186
  • Publisher: 工学図書株式会社
• [Patent(Industrial Property Rights)] 細胞培養デバイス (2012)
  • Inventor(s): 藤山陽一、田川陽一
  • Industrial Property Rights Holder: 島津製作所・東京工業大学
  • Industrial Property Number: 特許、特願2012-030204
  • Filing Date: 2012-02-15
• [Patent(Industrial Property Rights)] 肝保護剤、医薬組成物、食品、細胞等の保護方法、および細胞等保護用組成物 (2011)
  • Inventor(s): 内沢秀光、田川陽一、斉藤ゆかり、玉井美保、白川和浩
  • Industrial Property Rights Holder: 青森産業技術センター・東京工業大学・白川商店
  • Industrial Property Number: 特許、特願2011-159586
  • Filing Date: 2011-07-21
• [Patent(Industrial Property Rights)] CELL CULTURE DEVICE AND CELL CULTURE METHOD(細胞培養デバイス及び細胞培養方法) (2010)
  • Inventor(s): 藤山陽一、田川陽一
  • Industrial Property Rights Holder: 島津製作所・東京工業大学
  • Industrial Property Number: 特許、PCT-JP2010/065585
  • Filing Date: 2010-09-10
  • Overseas
• [Patent(Industrial Property Rights)] 細胞培養デバイス、細胞培養システム、及び細胞培養方法 (2010)
  • Inventor(s): 藤山陽一、田川陽一
  • Industrial Property Rights Holder: 島津製作所・東京工業大学
  • Industrial Property Number: 特許、特願2010-118960
  • Filing Date: 2010-05-25