Basic studies into development of novel preventive and regenerative therapy for hepatocarcinogenic cirrhosis using bone marrow-derived cells having redox-regulatory capacity

• Project/Area Number: 24790703
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Yamaguchi University
• Principal Investigator: TAKAMI Taro 山口大学, 医学(系)研究科(研究院), 講師 (60511251)
• Research Collaborator: QUINTANILHA Luiz Fernand 山口大学, 大学院医学系研究科, 助教研究者
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝硬変症 / 肝再生療法 / 骨髄細胞 / 酸化ストレス / 肝発癌 / 肝線維化

Research Abstract

We previously developed autologous bone marrow cell infusion (ABMi) therapy, which is a method of liver regeneration for liver cirrhotic patients using non-cultured autologous whole bone marrow cells, and reported the efficacy and safety of this approach. This ABMi therapy was officially approved as an "Advanced Medical Technology B" in Japan. We also reported that frequent bone marrow cell infusion contributed to suppressed tumor initiation during hepatocarcinogenesis. In these studies, we confirmed that hepatocytes co-cultured with bone marrow derived mesenchymal stem cells (MSCs) had lower levels of oxidative stress, and that cirrhotic mice treated with MSCs showed lower levels of liver fibrosis, higher serum antioxidant activity, and lower levels of hepatic malondialdehyde content. These results strongly indicate that cultured BMCs are a stem cell source in liver regeneration therapy for cirrhotic patients.

Research Products

• [Journal Article] Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo (2013)
  • Author(s): Quintanilha LF, Takami T, Hirose Y, Fujisawa K, Murata Y, Yamamoto N, Goldenberg RC, Terai S, Sakaida I
  • Journal Title: Hepatol Res. Volume: [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Improvement of liver fibrosis by infusion of cultured cells derived from human bone marrow (2013)
  • Author(s): Tanimoto H, Terai S, Takami T, Murata Y, Fujisawa K, Yamamoto N, Sakaida I
  • Journal Title: Cell Tissue Res. Volume: [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Bone-marrow-derived cells cultured in serum-free medium reduce liver fibrosis and improve liver function in carbon-tetrachloride-treated cirrhotic mice (2013)
  • Author(s): Iwamoto T, Terai S, Hisanaga T, Takami T, Yamamoto N, Watanabe S, Sakaida I
  • Journal Title: Cell Tissue Res. Volume: 351(3) Pages: 487-495
  • Peer Reviewed
• [Journal Article] Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo. (2013)
  • Author(s): Quintanilha LF, Takami T, Hirose Y, Fujisawa K, Murata Y, Yamamoto N, Goldenberg RC, Terai S, Sakaida I.
  • Journal Title: Hepatol Res. Volume: - Issue: 10
  • DOI: 10.1111/hepr.12204
  • Peer Reviewed
• [Journal Article] Improvement of liver fibrosis by infusion of cultured cells derived from human bone marrow. (2013)
  • Author(s): Tanimoto H, Terai S, Taro T, Murata Y, Fujisawa K, Yamamoto N, Sakaida I.
  • Journal Title: Cell Tissue Res. Volume: 354(3) Issue: 3 Pages: 717-28
  • DOI: 10.1007/s00441-013-1727-2
  • Peer Reviewed
• [Journal Article] Bone-marrow-derived cells cultured in serum-free medium reduce liver fibrosis and improve liver function in carbon-tetrachloride-treated cirrhotic mice. (2013)
  • Author(s): Iwamoto T, Terai S, Hisanaga T, Takami T, Yamamoto N, Watanabe S, Sakaida I.
  • Journal Title: Cell Tissue Res. Volume: 351(3) Issue: 3 Pages: 487-95
  • DOI: 10.1007/s00441-012-1528-z
  • Peer Reviewed
• [Journal Article] 肝臓の再生療法 (2013)
  • Author(s): 高見 太郎、寺井 崇二、坂井田 功
  • Journal Title: Annual Review消化器2013 Volume: - Pages: 196-202
• [Journal Article] 骨髄細胞投与による肝硬変症に対する肝再生・発癌抑制療法 (2013)
  • Author(s): 高見 太郎、前田 雅喜、寺井 崇二、坂井田 功
  • Journal Title: 月刊 消化器内科 Volume: 56(3) Pages: 324-330
• [Journal Article] 肝臓修復再生療法の評価 (2013)
  • Author(s): 高見 太郎、寺井 崇二、坂井田 功
  • Journal Title: 再生医療における臨床研究と製品開発 Volume: - Pages: 418-421
• [Journal Article] Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis. (2013)
  • Author(s): Saeki I, Terai S, Fujisawa K, Takami T, Yamamoto N, Matsumoto T, Hirose Y, Murata Y, Yamasaki T, Sakaida I.
  • Journal Title: J Gastroenterol. Volume: -
  • NAID: 10031184064
  • Peer Reviewed
• [Journal Article] Advanced therapies using autologous bone marrow cells for chronic liver disease (2012)
  • Author(s): Takami T, Terai S, Sakaida I
  • Journal Title: Discov Med. Volume: 14(74) Pages: 7-12
  • Peer Reviewed
• [Journal Article] Stem cell therapy in chronic liver disease (2012)
  • Author(s): Takami T, Terai S, Sakaida I
  • Journal Title: Curr Opin Gastroenterol. Volume: 28(3) Pages: 203-208
  • Peer Reviewed
• [Journal Article] Autologous bone marrow cell infusions suppress tumor initiation in hepatocarcinogenic mice with livercirrhosis (2012)
  • Author(s): Maeda M, Takami T, Terai S, Sakaida I
  • Journal Title: J Gastroenterol Hepatol. Volume: 27(Suppl2) Pages: 104-111
  • Peer Reviewed
• [Journal Article] Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy (2012)
  • Author(s): Terai S, Tanimoto H, Maeda M, Zaitsu J, Hisanaga T, Iwamoto T, Fujisawa K, Mizunaga Y, Matsumoto T, Urata Y, Marumoto Y, Hidaka I, Ishikawa T, Yokoyama Y, Aoyama K, Tsuchiya M, Takami T, Omori K, Yamamoto N, Segawa M, Uchida K, Yamasaki T, Okita K, Sakaida I
  • Journal Title: J Gastroenterol. Volume: 47(5) Pages: 491-497
  • NAID: 10030650365
  • Peer Reviewed
• [Journal Article] Advanced therapies using autologous bone marrow cells for chronic liver disease. (2012)
  • Author(s): Takami T, Terai S, Sakaida I.
  • Journal Title: Discov Med. Volume: 14(74) Pages: 7-12
  • Peer Reviewed
• [Journal Article] Stem cell therapy in chronic liver disease. (2012)
  • Author(s): Takami T, Terai S, Sakaida I.
  • Journal Title: Curr Opin Gastroenterol. Volume: 28(3) Pages: 203-208
  • Peer Reviewed
• [Journal Article] Autologous bone marrow cell infusions suppress tumor initiation in hepatocarcinogenic mice with liver cirrhosis. (2012)
  • Author(s): Maeda M, Takami T, Terai S, Sakaida I.
  • Journal Title: J Gastroenterol Hepatol. Volume: 27(Suppl 2) Pages: 104-111
  • Peer Reviewed
• [Journal Article] Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy. (2012)
  • Author(s): Terai S, Tanimoto H, Maeda M, Zaitsu J, Hisanaga T, Iwamoto T, Fujisawa K, Mizunaga Y, Matsumoto T, Urata Y, Marumoto Y, Hidaka I, Ishikawa T, Takami T, et al.
  • Journal Title: J Gastroenterol. Volume: 47(5) Pages: 491-497
  • NAID: 10030650365
  • Peer Reviewed
• [Journal Article] Effect of transcatheter arterial infusion chemotherapy using iodized oil and degradable starch microspheres for hepatocellular carcinoma. (2012)
  • Author(s): Yamasaki T, Saeki I, Harima Y, Zaitsu J, Maeda M, Tanimoto H, Iwamoto T, Hidaka I, Urata Y, Ishikawa T, Takami T, Yamaguchi Y, Uchida K, Terai S, Sakaida I.
  • Journal Title: J Gastroenterol. Volume: 47(6) Pages: 715-722
  • NAID: 10030802839
  • Peer Reviewed
• [Journal Article] 肝臓の再生治療 (2012)
  • Author(s): 高見太郎、寺井崇二、坂井田 功
  • Journal Title: Annual Review消化器2012 Volume: - Pages: 192-197
• [Journal Article] 肝再生医学のトランスレーショナル・リサーチ (2012)
  • Author(s): 高見太郎、寺井崇二、坂井田 功
  • Journal Title: 肝疾患レビュー2012-2013 Volume: - Pages: 69-75
• [Journal Article] 肝硬変診療のトピックス「自己骨髄細胞を用いた肝修復再生療法の現状」 (2012)
  • Author(s): 高見太郎、寺井崇二、坂井田 功
  • Journal Title: medicina Volume: 49(7) Pages: 1238-1239
• [Journal Article] 肝硬変Update「自己骨髄細胞投与による肝修復再生療法」 (2012)
  • Author(s): 高見太郎、坂井田 功
  • Journal Title: 医学のあゆみ Volume: - Pages: 804-808
• [Journal Article] マウス肝硬変高発癌モデルにおける自己骨髄細胞投与の影響 (2012)
  • Author(s): 前田雅喜、高見太郎、藤澤浩一、山本直樹、寺井崇二、坂井田 功
  • Journal Title: 分子生物学が可能とした個別化医療（第19回浜名湖シンポジウム） Volume: - Pages: 165-172
• [Journal Article] 肝硬変発癌モデルにおける自己骨髄細胞投与の影響 (2012)
  • Author(s): 前田雅喜、高見太郎、山本直樹、寺井崇二、坂井田 功
  • Journal Title: G.I. Research Volume: 20(4) Pages: 368-369
• [Presentation] Liver regeneration therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells with stabilization of redox homeostasis (2014)
  • Author(s): Takami T, Terai S, Sakaida I
  • Organizer: Choshu International Liver Symposium 2014
  • Place of Presentation: Ube, Yamaguchi, Japan (ANA Crowne Plaza Hotel UBE)
  • Year and Date: 2014-01-25
• [Presentation] 自己骨髄細胞による肝臓再生療法の取り組み (2013)
  • Author(s): 高見 太郎、寺井崇二、坂井田 功
  • Organizer: 第40回日本肝臓学会西部会
  • Place of Presentation: (長良川国際会議場、岐阜市、岐阜)
  • Year and Date: 2013-12-06
• [Presentation] ヒト骨髄由来および脂肪組織由来間葉系幹細胞における組織因子および IL-8の発現検討 (2013)
  • Author(s): 高見太郎、寺井崇二、村田泰彦、坂井田功
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: (京王プラザホテル、新宿区、東京都)
  • Year and Date: 2013-06-06
• [Presentation] 肝再生修復療法としての培養ヒト骨髄間葉系細胞投与療法のメカニズム解析 (2013)
  • Author(s): 高見 太郎、寺井 崇二、村田泰彦、廣瀬 恵一、藤澤 浩一、山本 直樹、坂井田 功
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: (京王プラザホテル、新宿区、東京都)
  • Year and Date: 2013-06-06
• [Presentation] 肝再生修復療法としての培養ヒト骨髄間葉系細胞投与療法のメカニズム解析 (2013)
  • Author(s): 高見 太郎、寺井 崇二、村田泰彦、Quintanilha LF、廣瀬 恵一、藤澤 浩一、山本 直樹、坂井田 功
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: (パシフィコ横浜、横浜市、神奈川県)
  • Year and Date: 2013-03-21
• [Presentation] 自己骨髄細胞による肝硬変に対する再生修復療法の現状と展望 (2013)
  • Author(s): 高見 太郎、寺井 崇二、坂井田 功
  • Organizer: 第32回日本画像医学会
  • Place of Presentation: (ホテルメトロポリタン東京、千代田区、東京都)
  • Year and Date: 2013-02-23
• [Presentation] The development of a less-invasive liver regeneration therapy using cultured bone marrow derived cells for cirrhotic patients (2013)
  • Author(s): Takami T, Terai S, Murata Y, Quintanilha LF, Hirose Y, Fujisawa K, Yamamoto N, Sakaida I
  • Organizer: Choshu International Liver Symposium 2013
  • Place of Presentation: Ube, Yamaguchi, Japan (ANA Crowne Plaza Hotel UBE)
  • Year and Date: 2013-02-09
• [Presentation] Basic studies for a less invasive liver regeneration therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells with stabilization of redox homeostasis (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Fujisawa K, Yamamoto N, Sakaida I
  • Organizer: The liver meeting 2013, AASLD
  • Place of Presentation: Washington D.C., USA.
• [Presentation] The development of a less-invasive liver regeneration therapy using cultured bone marrow derived cells for cirrhotic patients (2013)
  • Author(s): Takami T, Terai S, Sakaida I
  • Organizer: JDDW2013
  • Place of Presentation: Shinagawa, Tokyo, Japan (Grand Prince Hotel New Takanawa, Pamir)
• [Presentation] Basic studies for a less invasive liver regeneration therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells with stabilization of redox homeostasis (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Fujisawa K, Yamamoto N, Sakaida I
  • Organizer: The 20th Annual Meeting of the Japanese Society for the Research of Hepatic Cells (20th JSRH)
  • Place of Presentation: Osaka, Japan( Osaka International ConventionCenter)
• [Presentation] Basic studies using human and canine bone marrow derived mesenchymal stem cells for the development of a less invasive liver regeneration therapy for liver cirrhotic patients (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Tanimoto H, Murata Y, Fujisawa K, Yamamoto N, Sakaida I
  • Organizer: The 11th Annual meeting of ISSCR
  • Place of Presentation: Boston, MA, USA.
• [Presentation] The development of a less-invasive liver regeneration therapy using cultured bone marrow derived cells for cirrhotic patient (2013)
  • Author(s): Takami T, Terai S, Sakaida I
  • Organizer: 2nd The International Conference on Gastroenterology & Urology
  • Place of Presentation: Northbrook, IL, USA.
• [Presentation] The development of a less-invasive liver regeneration therapy using cultured bone marrow derived cells for cirrhotic patients. (2013)
  • Author(s): Takami T, Terai S, Sakaida I.
  • Organizer: 2nd International Conference on Gastroenterology& Urology
  • Place of Presentation: Northbrook, IL USA
• [Presentation] Basic studies for a less invasive liver regeneration therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells with stabilization of redox homeostasis. (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Fujisawa K, Yamamoto N, Sakaida I.
  • Organizer: The 20th Annual Meeting of the Japanese Society for the Research of Hepatic Cells
  • Place of Presentation: Osaka, Japan（大阪国際会議場）
• [Presentation] The development of a less-invasive liver regeneration therapy using cultured bone marrow derived cells for cirrhotic patients. (2013)
  • Author(s): Takami T, Terai S, Sakaida I.
  • Organizer: JDDW2014
  • Place of Presentation: Shinagawa, Tokyo, Japan（品川プリンスホテル）
• [Presentation] Basic studies using human and canine bone marrow derived mesenchymal stem cells for the development of a less invasive liver regeneration therapy for liver cirrhotic patients. (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Tanimoto H, Murata Y, Fujisawa K, Yamamoto N, Sakaida I.
  • Organizer: 11th Annual meeting of ISSCR
  • Place of Presentation: Boston, MA USA
• [Presentation] Basic studies for a less invasive liver regeneration therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells with stabilization of redox homeostasis. (2013)
  • Author(s): Takami T, Terai S, Quintanilha LF, Fujisawa K, Yamamoto N, Sakaida I.
  • Organizer: The liver meeting 2013, AASLD
  • Place of Presentation: Washington D.C. USA
• [Presentation] ヒト骨髄由来および脂肪組織由来間葉系幹細胞における組織因子およびIL-8の発現検討 (2013)
  • Author(s): 高見 太郎、寺井 崇二、村田 泰彦、Quintanilha LF、廣瀬 恵一、藤澤 浩一、山本 直樹、坂井田 功
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] 自己骨髄細胞による肝臓再生療法の取り組み (2013)
  • Author(s): 高見 太郎、寺井 崇二、坂井田 功
  • Organizer: 第40回日本肝臓学会西部会
  • Place of Presentation: 長良川国際会議場（岐阜県岐阜市）
• [Presentation] 肝再生修復療法としての培養ヒト骨髄間葉系細胞投与療法のメカニズム解析 (2013)
  • Author(s): 高見 太郎、寺井 崇二、村田 泰彦、廣瀬 恵一、藤澤 浩一、山本 直樹、坂井田 功
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] Bone marrow cell infusions suppress hepatocarcinogenesis in N-nitrosodiethylamine-and carbon tetrachloride-induced hepatocarcinogenic mice with liver cirrhosis (2012)
  • Author(s): Takami T, Terai S, Maeda M, Hirose Y, Fujisawa K, Yamamoto N, Sakaida I.
  • Organizer: 10th ISSCR Annual meeting
  • Place of Presentation: Yokohama, Kanagawa, Japan（パシフィコ横浜）
• [Presentation] Basic studies for the development of a less invasive liver regeneration therapy using thermoreactive organic/inorganic nanocomposite gels-cultured bone marrow derived cells (2012)
  • Author(s): Takami T, Terai S, Hirose Y, Fujisawa K, Yamamoto N, Takehisa T, Takada T, Haraguchi K, Sakaida I.
  • Organizer: 10th ISSCR Annual meeting
  • Place of Presentation: Yokohama, Kanagawa, Japan（パシフィコ横浜）
• [Presentation] Bone marrow cell infusions suppress hepatocarcinogenesis in N-nitrosodiethylamine-and carbon tetrachloride-induced hepatocarcinogenic mice with liver cirrhosis (2012)
  • Author(s): Takami T, Terai S, Maeda M, Sakaida I
  • Organizer: FASEB meeting
  • Place of Presentation: Snowmass village, CO, USA
• [Presentation] Clear Cell type の肝細胞癌の一例 (2012)
  • Author(s): 高見太郎、土屋昌子、石川 剛、寺井崇二、山崎隆弘、坂井田 功
  • Organizer: 第85回日本超音波医学会総会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都品川区）
• [Presentation] 有機-無機・ナノハイブリッドシステムによる低侵襲肝再生修復療法の開発のための基礎的検討 (2012)
  • Author(s): 高見太郎、寺井崇二、廣瀬恵一、藤澤浩一、山本直樹、坂井田 功
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
• [Presentation] 肝細胞癌治療に対する鉄キレート剤の新規治療薬としての可能性 (2012)
  • Author(s): 山本直樹、寺井崇二、岩本拓也、高見太郎、内田耕一、山崎隆弘、仁科博史、坂井田 功
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
• [Presentation] 肝硬変に対する有機-無機・ナノハイブリッドシステムによる低侵襲再生修復療法の開発のための基礎研究 (2012)
  • Author(s): 高見太郎、寺井崇二、谷本治子、廣瀬恵一、藤澤浩一、山本直樹、武久 敢、高田哲生、原口和敏、坂井田 功
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] 肝硬変に対する自己骨髄細胞投与(ABMi)療法における肝発癌への影響の基礎的検討 (2012)
  • Author(s): 高見太郎、寺井崇二、前田雅喜、廣瀬恵一、藤澤浩一、山本直樹、坂井田 功
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] 骨髄細胞投与による酸化ストレス制御を介した肝発癌抑制メカニズムの解明 (2012)
  • Author(s): 高見太郎、寺井崇二、坂井田 功
  • Organizer: 第20回JDDW2012
  • Place of Presentation: 神戸国際展示場（兵庫県神戸市）
• [Presentation] 骨髄細胞投与による肝発癌抑制メカニズムの解析 (2012)
  • Author(s): 高見 太郎、寺井 崇二、坂井田 功
  • Organizer: 第19回肝細胞研究会
  • Place of Presentation: 札幌医科大学（北海道札幌市）
• [Presentation] 骨髄間葉系細胞による低侵襲肝修復療法のための基礎研究 (2012)
  • Author(s): 高見 太郎、寺井 崇二、谷本 治子、Quintanilha LF、廣瀬 恵一、藤澤 浩一、山本 直樹、坂井田 功
  • Organizer: 第26回肝類洞壁細胞研究会学術集会
  • Place of Presentation: ANAクラウンプラザホテル宇部（山口県宇部市）
• [Book] Liver Resident Stem Cell (2012)
  • Author(s): Takiya CM, Paredes BD, Quintanilha LF, Dias GS, Pinheiro LA, Takami T, Terai S, Sakaida I, Regina SG
  • Publisher: ELSEVIER
• [Book] Resident Stem Cells and Regenerative Therapy (2012)
  • Author(s): Takiya CM, Paredes BD, Mesquita LF, Dias GS, Faccioli LA, Takami T, Terai S, Sakaida I, Goldenberg RC.
  • Publisher: ELSEVIER