Development of super functional liver model based on developmental information

• Project/Area Number: 18300161
• 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 Tokyo Institute of Technology, フロンティア研究センター, 准教授 (70262079)
• Co-Investigator(Kenkyū-buntansha): 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) ; NAGAOKA Masato 東京工業大学, 大学院・生命理工学研究科, 助教 (90397050)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,520,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥2,220,000); Fiscal Year 2008: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2007: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2006: ¥7,900,000 (Direct Cost: ¥7,900,000)
• Keywords: 細胞 / 組織工学 / 肝臓 / 肝組織 / バイオチップ / 人工肝臓 / 内皮細胞 / EHSゲル / ES細胞 / iPS細胞 / 肝機能 / 赤色蛍光タンパク質 / 肝細胞 / チップ / 赤色蛍光 / トランスジェニックマウス / 肝実質細胞 / 器官形成

Research Abstract

個体発生時の肝臓形成を模倣したマウスES細胞から肝組織へ分化誘導する我々独自の手法を応用して、肝細胞チップではなく、肝組織チップを開発することが本研究の目的であった。胚様体またはES細胞由来肝組織を培養できる蓋開閉型マイクロ培養装置の開発を行い、肝機能を測定することに成功した。また、ES細胞由来肝組織のほか、内皮細胞ネットワーク管状構造の周囲に初代培養肝実質細胞が接着する類洞肝組織構造のマイクロ培養装置の開発にも成功した。以上のことから、肝組織チップが薬物代謝や毒性試験へ応用できる可能性を示すことができた。

Research Products

• [Journal Article] In vitro reprogramming of adult hepatocytes into insulin producing cells without viral bectors (2009)
  • Author(s): Motoyama, H., S. Ogawa, A. Kubo, S. Miwa, J. Nakayama, Y. Tagawa, and S. Miyagawa
  • Journal Title: Biochem. Biophys. Res. Commun
  • Peer Reviewed
• [Journal Article] Deficiency of Tumor Necrosis Factor-α and Interferon-γ in bone marrow cells synergistically inhibits neointimal formation following vascular injury (2008)
  • Author(s): Maruyama, H., M. Takahashi, M. Takamoto, Y. Shiba, H. Ise, J. Koyama, Y. Tagawa, Y. Iwakura, and U. Ikeda
  • Journal Title: Cardiovasc Res 80 Pages: 175-180
  • Peer Reviewed
• [Journal Article] Hepatoprotective effect of vitamin b(12) on dimethylnitrosamine induced liver injury (2008)
  • Author(s): Isoda, K., N. Kagaya, S. Akamatsu, S. Hayashi, M. Tamesada, A. Watanabee, M. Kobayashi, Y. Tagawa, M. Kondoh, M. Kawase, and K. Yagi
  • Journal Title: Biol. Pharm. Bull 31 Pages: 309-311
  • Peer Reviewed
• [Journal Article] Deficiency of tumour necrosis factor-a and interferon-g in bone marrow cells synergistically inhibits neointimal formation following vascular injury (2008)
  • Author(s): H. Murayama, M. Takahashi, M. Takamoto, Y. Shiba, H. Ise, J. Koyama, Y. Tagawa, Y. Iwakura, U. Ikeda
  • Journal Title: Cardiovascular Research 80 Pages: 175-180
  • Peer Reviewed
• [Journal Article] 胚性幹細胞研究におけるバイオマテリアル-高性能・多機能肝臓モデルの作製を目指して (2008)
  • Author(s): 田川陽一
  • Journal Title: バイオマテリアル-生体材料- 26 Pages: 325-329
  • NAID: 10021141296
• [Journal Article] Hepatoprotective effect of vitamin B_<12> on dimethylnitrosamine-induced liver injury (2008)
  • Author(s): Katsuhiro Isoda, 他10名
  • Journal Title: Biol. Pharm. Bull. 31 Pages: 309-311
  • Peer Reviewed
• [Journal Article] Primary hepatocyte survival on non integrin recognizable matrices without the activation of Akt signaling (2007)
  • Author(s): Hoshiba, T., H. Nagahara, C. S. Cho, Y. Tagawa, and T.Akaike
  • Journal Title: Biomaterials 28 Pages: 1093-1104
  • Peer Reviewed
• [Journal Article] トランスジェニック動物作製のための遺伝子導入方法 (2007)
  • Author(s): 田川陽一
  • Journal Title: 再生医療 6 Pages: 134-139
• [Journal Article] Primary hepatocyte survival on non-integrin-recognizable matrices without the activation of Akt signaling. (2007)
  • Author(s): Hoshiba, T., H.Nagahara, C.S.Cho, Y.Tagawa, T.Akaike
  • Journal Title: Biomaterials 28 Pages: 1093-1104
• [Journal Article] Characterization of cytochrome P450 expression in murine embryonic stem cell derived hepatic tissue system (2006)
  • Author(s): Tsutsui, M., S. Ogawa, Y. Inada, E. Tomioka, A. Kamiyoshi, S. Tanaka, T. Kishida, M. Nishiyama, M. Murakami, J. Kuroda, Y. Hashikura, S. Miyagawa, F. Satoh, N. Shibata, and Y. Tagawa*
  • Journal Title: Drug Metab. Dispos 34 Pages: 696-701
  • Peer Reviewed
• [Journal Article] Collagen synthesis is required for ascorbic acid enhaced differentiation of mouse embryonic stem cells into cardiomyocytes (2006)
  • Author(s): Sato, H., M. Takahashi, H. Ise, A. Yamada, S. Hirose, Y. Tagawa, H. Morimoto, A. Izawa, U. Ikeda
  • Journal Title: Biochem. Biophys. Res. Commun 342 Pages: 107-112
  • Peer Reviewed
• [Journal Article] ICOS-ligand B7-H2, expressed on Human type II alveolar epithelial cells, plays a role in pulmonary host defense system (2006)
  • Author(s): Qian,X, K. Agematsu, G. J. Freeman, Y. Tagawa, K. Sugane, T. Hayashi
  • Journal Title: Eur. J. Immunol 36 Pages: 906-918
  • Peer Reviewed
• [Journal Article] Endogenous aCGRP protects against concanavalin A induced hepatitis in mice (2006)
  • Author(s): Kamiyoshi, A., T. Sakurai, Y. Ichikawa-Shindo, J. Fukuchi, H. Kawate, S. Muto, Y. Tagawa, and T. Shindo
  • Journal Title: Biochem. Biophys. Res. Commun 342 Pages: 152-158
  • Peer Reviewed
• [Journal Article] The role of gamma interferon in acquired host resistance against Staphylococcus aureus infection in mice (2006)
  • Author(s): Sasaki, S, Y. Tagawa, Y. Iwakura, and A. Nakane
  • Journal Title: FEMS Immunol. Med. Microbiol 46 Pages: 367-374
  • Peer Reviewed
• [Journal Article] The role of gamma interferon in acquired host resistance against Staphylococcus aureus infection in mice. (2006)
  • Author(s): Sasaki, S, Y.Tagawa, Y.Iwakura, A.Nakane
  • Journal Title: FEMS Immunol. Med. Microbiol. 46 Pages: 367-374
• [Presentation] Construction of Artificial Liver System Containing Multiple Cell Sorts and Biomaterials (2009)
  • Author(s): M. Tamai, S. Hosoya, T. Akaike, E. Adachi, Y. Tagawa
  • Organizer: SNU-TIT-TU-UT Joint Bioengineering Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-03-28
• [Presentation] Construction of Artificial Liver System Containing Multiple Cell Sorts and Biomaterials (2009)
  • Author(s): Miho TAMAI, Satoshi HOSOYA, Toshihiro AKAIKE, Eijiro ADACHI, Yoh-ichi TAGAWA
  • Organizer: SNU-TIT-TU-UT Joint Bioengineering Symposium
  • Place of Presentation: Seoul
  • Year and Date: 2009-03-28
• [Presentation] Developmental Engineering and Regenerative Medicine (2009)
  • Author(s): Y. Tagawa
  • Organizer: SNU-TIT-TU-UT Joint Bioengineering Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-03-27
• [Presentation] Developmental Engineering and Regenerative Medicine (2009)
  • Author(s): Y. TAGAWA
  • Organizer: SNU-TIT-TU-UT Joint Bioengineering Symposium
  • Place of Presentation: Seoul
  • Year and Date: 2009-03-27
• [Presentation] Super-functional Liver Model based on Developmental Engineering and Biomaterials (2009)
  • Author(s): Y. Tagawa
  • Organizer: 2009 China Japan Regenerative Medical Techniques Forum Shanghai
  • Place of Presentation: China
  • Year and Date: 2009-03-18
• [Presentation] Green-Red 蛍光システムを用いた幹細胞移植実験 (2009)
  • Author(s): 柳 濟榮、Siswanto Antony、三田村圭祐、赤池敏宏、神吉昭子、田川陽一
  • Organizer: 日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-03-06
• [Presentation] 高密度培養法を用いた複合型人工肝臓の再構成 (2009)
  • Author(s): 細谷智、岩城啓修、菊池史郎、上野正樹、玉井美保、田川陽一、渡辺昌彦、安達栄次郎
  • Organizer: 日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-03-06
• [Presentation] Green-Red蛍光システムを用いた幹細胞移植実験 (2009)
  • Author(s): 柳 濟榮, Siswanto Antony, 三田村圭祐, 赤池敏宏, 神吉昭子, 田川陽一
  • Organizer: 日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-03-06
• [Presentation] マウス門脈結紮モデルより分離した肝前駆細胞の解析と分化誘導 (2009)
  • Author(s): 酒井浩司、田川陽一、本山博章、宮川眞一
  • Organizer: 日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-03-05
• [Presentation] Super-functional Liver Model based on Developmental Engineering and Biomaterials (2009)
  • Author(s): Yoh-ichi TAGAWA
  • Organizer: 2009 China-Japan Regenerative Medical Techniques
  • Place of Presentation: Shanghai
• [Presentation] EMBRYONIC STEM CELLS IN DRUG METABOLISM AND TOXICOLOGY (2008)
  • Author(s): Y. Tagawa
  • Organizer: 2008 Annual Conference of Tissue Engineering and Regenerative Medicine International Society-Asian Pacific Region (2008 TERMIS-AP)
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2008-11-08
• [Presentation] EMBRYONIC STEM CELLS IN DRUG METABOLISM AND TOXICOLOGY (2008)
  • Author(s): Yoh-ichi TAGAWA
  • Organizer: 2008 Annual Conference of Tissue Engineering and Regenerative Medicine International Society-Asian Pacific Region (2008 TERMIS-AP)
  • Place of Presentation: Taiwan
  • Year and Date: 2008-11-08
• [Presentation] Ectopic Expression of Pdx1 and Ngn3 Are Highly Up Regulated in Regenerative Liver (2008)
  • Author(s): H. Motoyama, S. Ogawa, S. Miyagawa, Y. TAGAWA
  • Organizer: and Which Contributed to Transdifferentiation of Liver To Pancreas 2008 Annual Conference of Tissue Engineering and Regenerative Medicine International Society-Asian Pacific Region (2008 TERMIS-AP)
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2008-11-06
• [Presentation] Development of the highly functional hepatic tissue through mimicking of liver construction (2008)
  • Author(s): M. Tamai, S. Kobayashi, and Y. Tagawa
  • Organizer: TOIN International Symposium on Biomedical Engineering 2008
  • Place of Presentation: Yokoyama
  • Year and Date: 2008-10-31
• [Presentation] Production of green mouse for somatic stem cell transplantation experiments (2008)
  • Author(s): J. Ryu, K. Mitamura, A. Siswanto, T. Akaike, Y. Tagawa
  • Organizer: TOIN International Symposium on Biomedical Engineering 2008
  • Place of Presentation: Yokoyama
  • Year and Date: 2008-10-31
• [Presentation] Production of green mouse for somatic stem cell transplantation experiments (2008)
  • Author(s): Je-young RYU, Keisuke MITAMURA, Antoni SISWANTO, Toshihiro AKAIKE, Yoh-ichi TAGAWA
  • Organizer: TOIN International Symposium on Biomedical Engineering 2008
  • Place of Presentation: Yokohama
  • Year and Date: 2008-10-31
• [Presentation] Development of the highly functional hepatic tissue through mimicking of liver construction (2008)
  • Author(s): Miho TAMAI. Shunsuke KOBAYASHI, Yoh-ichi TAGAWA
  • Organizer: TOIN International Symposium on Biomedical Engineering 2008
  • Place of Presentation: Yokohama
  • Year and Date: 2008-10-31
• [Presentation] ES細胞における金属イオンの動態 (2008)
  • Author(s): 相川博明、川瀬雅也、斉藤直、赤池敏宏、田川陽一
  • Organizer: 第60回日本生物工学会
  • Place of Presentation: 仙台
  • Year and Date: 2008-08-28
• [Presentation] In vitro reconstruction of hepatic tissue structure (2008)
  • Author(s): Y. Tagawa, S. Kobayashi, H. Okuyama, T. Shindo, T. Akaike
  • Organizer: The 8th World Biomaterials Congress
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2008-05-29
• [Presentation] Roles of donor, recipient cells and environmental factors in the formation of embryonic stem cell derived teratoma in mice (2008)
  • Author(s): K. Mitamura, A. Siswanto, J. Ryu, A. Kamiyoshi, E. Adachi, T. Akaike, Y. Tagawa
  • Organizer: The 8th World Biomaterials Congress
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2008-05-29
• [Presentation] Grreen-Red 蛍光システムを用いたES細胞由来テラトーマにおける組織形成の解析 (2008)
  • Author(s): 三田村圭祐、柳濟榮、Siswanto Antony、神吉昭子、安達栄治郎、赤池敏宏、田川陽一
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-14
• [Presentation] 固定化N-カドヘリンモデルによるP19細胞の分化制御 (2008)
  • Author(s): 岳暁珊、田川陽一、赤池敏宏、竹内純、長岡正人
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-14
• [Presentation] 肝実質細胞-管化内皮細胞共培養法の確立とその肝機能解析 (2008)
  • Author(s): 小林俊介、奥山久嗣、新藤隆行、赤池敏宏、田川陽一
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-13
• [Presentation] In vitro reconstruction of hepatic tissue structure (2008)
  • Author(s): Yoh-ichi TAGAWA, Shunsuke KOBAYASHI, Hisashi OKUYAMA, Takayuki SHINDO, Toshihiro AKAIKE
  • Organizer: The 8th World Biomaterials Congress, Amsterdam
  • Place of Presentation: Amsterdam
• [Presentation] Roles of donor, recipient cells and environmental factors in the formation of embryonic stem cell-derived teratoma in mice (2008)
  • Author(s): Keisuke MITAMURA, Antoni SISWANTO, Jeyoung RYU, Akiko KAMIYOSHI, Eijiro ADACHI, Toshihiro AKAIKE, Yoh-ichi TAGAW
  • Organizer: The 8th World Biomaterials Congress, Amsterdam
  • Place of Presentation: Amsterdam
• [Presentation] Grreen-Red蛍光システムを用いたES細胞由来テラトーマにおける組織形成の解析 (2008)
  • Author(s): 三田村圭祐, 他6名
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋
• [Presentation] 管化内皮細胞共培養システムを用いた肝実質細胞との共培養における肝機能の解析 (2007)
  • Author(s): 小林俊介、奥山久嗣、新藤隆行、赤池敏宏、田川陽一
  • Organizer: 第30回日本分子生物学会および第80回日本生化学学会合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] 管化内皮細胞共培養システムを用いた肝実質細胞との共培養における肝機能の解析 (2007)
  • Author(s): 小林俊介, 他6名
  • Organizer: 第30回日本分子生物学会および第80回日本生化学学会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] ES細胞を用いたinvitrro 肝組織構築におけるバイオマテリアルへの期待 (2007)
  • Author(s): 田川陽一
  • Organizer: 第29回日本バイオマテリアル学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-27
• [Presentation] 管化内皮細胞培養システムを用いた肝実質細胞との共培養における肝機能の解析 (2007)
  • Author(s): 小林俊介、藤山陽一、奥山久嗣、新藤隆行、赤池敏宏、小関英一、田川陽一
  • Organizer: 第29回日本バイオマテリアル学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-27
• [Presentation] ES細胞を用いたin vitrro肝組織構築におけるバイオマテリアルへの期待 (2007)
  • Author(s): 田川陽一
  • Organizer: 第29回日本バイオマテリアル学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-27
• [Presentation] Donor and recipient cells in micee can be visualized and clearrly discriminated by using Breen Red fluorescent system (2007)
  • Author(s): K. Mitamura, A. Siswanto, J. Ryu, A. Kamiyoshi, E. Adachi, T. Akaike, Y. Tagawa
  • Organizer: TOIN International Symposium on Biomedical Engineering 2007
  • Place of Presentation: Yokohama
  • Year and Date: 2007-11-02
• [Presentation] Donor and recipient cells in micee can be visualized and clearrly discriminated by using Breen-Red fluorescent system (2007)
  • Author(s): Keisuke Mitamura, 他6名
  • Organizer: TOIN International Symposium on Biomedical Engineering 2007
  • Place of Presentation: Yokohama
  • Year and Date: 2007-11-02
• [Presentation] Liver Model Derived from Embryonic Stem Cells (2007)
  • Author(s): Y. Tagawa
  • Organizer: 1^<st> International symposium on cancer therrapy and regenerative medicine 2007
  • Place of Presentation: Sizuoka
  • Year and Date: 2007-10-06
• [Presentation] Liver Model Derived from Embryonic Stem Cells (2007)
  • Author(s): Yoh-ichi TAGAWA
  • Organizer: 1st International symposium on cancer ther and regenerative medicine
  • Place of Presentation: Shizuoka
  • Year and Date: 2007-10-06
• [Presentation] サイトカイン固定化型マイクロビーズによる細胞への局所刺激誘導と細胞の動的挙動解析 (2007)
  • Author(s): 荒津史裕、原田伊知郎、田川陽一、赤池敏宏
  • Organizer: 第72回インターフェロン・サイトカイン学会
  • Place of Presentation: 京都
  • Year and Date: 2007-07-05
• [Presentation] ES細胞を用いた肝再生医療への可能性-ES細胞由来肝組織の肝機能解析- (2007)
  • Author(s): 小川真一郎、田川陽一
  • Organizer: 第6回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-03-13
• [Presentation] ES細胞から肝臓を造る (2007)
  • Author(s): 田川陽一
  • Organizer: 第6回日本再生医療学会総会 市民公開講座 再生医療最前線-臓器傷害と機能の再生-
  • Place of Presentation: 横浜
  • Year and Date: 2007-03-12
• [Book] 「幹細胞の分化誘導とその応用」ブッカーズ (2009)
  • Author(s): 田川陽一、小川真一郎、玉井美保、小林俊介
  • Publisher: 高性能・多機能肝臓モデルの作製を目指して
• [Book] 「幹細胞の分化誘導とその応用」ブッカーズ (2009)
  • Author(s): 後藤光昭、田川陽一、赤池敏弘
  • Publisher: 新規バイオマテリアルを中心とした幹細胞の培養・文化誘導技術と誘導された肝細胞による薬物毒性評価用チップの可能性
• [Book] 幹細胞の分化誘導とその応用高性能・多機能肝臓モデルの作製を目指して (2009)
  • Author(s): 田川陽一, 小川真一郎, 玉井美保, 小林俊介
  • Publisher: ブッカーズ
• [Book] 幹細胞の分化誘導とその応用新規バイオマテリアルを中心とした幹細胞の培養・分化誘導技術と誘導された肝細胞による薬物毒性評価用チップの可能性 (2009)
  • Author(s): 後藤光昭, 田川陽一, 赤池敏宏
  • Publisher: ブッカーズ
• [Book] バイオ系のための基礎化学問題集 (2008)
  • Author(s): 田川陽一、他30名
  • Publisher: 講談社
• [Book] バイオ系のための基礎化学問題集 (2008)
  • Author(s): 田川陽一, 他30名
  • Total Pages: 280
  • Publisher: 講談社
• [Patent(Industrial Property Rights)] バイオデバイス (2009)
  • Inventor(s): 田川陽一, 他2名
  • Industrial Property Rights Holder: 東京工業大学および島津製作所
  • Filing Date: 2009-02-03
  • Overseas
• [Patent(Industrial Property Rights)] バイオデバイス (2008)
  • Inventor(s): 藤山陽一、田川陽一、小林俊介
  • Industrial Property Number: 2008-023638
  • Filing Date: 2008
• [Patent(Industrial Property Rights)] バイオデバイス (2008)
  • Inventor(s): 田川陽一、他2名
  • Industrial Property Rights Holder: 東京工業大学と島津製作所
  • Industrial Property Number: 2008-023638
  • Filing Date: 2008-02-04