Regeneration of Fibrotic Liver through Modulation of Hepatic Stem Cell Niche and Differentiation of Bone Marrow Stem Cells

• Project/Area Number: 22390152
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokai University
• Principal Investigator: INAGAKI Yutaka 東海大学, 医学部, 教授 (80193548)
• Co-Investigator(Kenkyū-buntansha): ASAHARA Takayuki 東海大学, 医学部, 教授 (20246200)
• Co-Investigator(Renkei-kenkyūsha): HOZUMI Katsuto 東海大学, 医学部, 准教授 (30246079)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2011: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2010: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 肝線維化 / 再生 / 幹前駆細胞 / Notch/Jagged-1シグナル / 肝線維症 / 肝再生 / Notch / Jagged-1 / 幹細胞

Research Abstract

Liver is considered to have a high potential of regeneration, but the presence of fibrosis suppresses the recovery of injured liver. Stem cells are utilized to compensate such impaired regeneration. We have been working on the Notch/Jagged-1 signal to link liver fibrosis and stem cell mobilization. Experiments using Jagged-1 knockout mice have revealed important roles of the signal in the development of normal liver as well as the regeneration of fibrotic liver. These results may eventually contribute to the development of a novel therapeutic strategy that suppresses liver fibrosis and accelerate regeneration of fibrotic liver.

Research Products

• [Journal Article] 今なぜ肝線維化研究が注目されているのか． (2013)
  • Author(s): 稲垣 豊
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 513-513
• [Journal Article] コラーゲン分子種と線維症形成へのかかわり． (2013)
  • Author(s): 住吉秀明
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 515-520
• [Journal Article] Interplay between bone marrow and liver in the pathogenesis of hepatic fibrosis (2012)
  • Author(s): Inagaki Y, Higashiyama R
  • Journal Title: Hepatol Res Volume: 42 Pages: 543-548
  • NAID: 10031144268
  • Peer Reviewed
• [Journal Article] Novel anti-fibrotic modalities for liver fibrosis: Molecular targeting and regenerative medicine in fibrosis therapy (2012)
  • Author(s): Inagaki Y, Higashiyama R, Higashi K
  • Journal Title: Gastroenterol Hepatol Volume: 27 Pages: 85-88
  • Peer Reviewed
• [Journal Article] 肝線維症治療の研究はどこまで進展したか? (2012)
  • Author(s): 稲垣 豊、中尾祥絵、瀧澤友里、他
  • Journal Title: 肝胆膵 Volume: 65 Pages: 253-260
• [Journal Article] Development of serum-free quality and quantity control culture of colonyforming endothelial progenitor cell for vasculogenesis (2012)
  • Author(s): Masuda H, Iwasaki H, Asahara T, et al
  • Journal Title: Stem Cells Transl Med Volume: 1 Pages: 160-171
  • Peer Reviewed
• [Journal Article] Interplay between bone marrow and liver in the pathogenesis of hepatic fibrosis. (2012)
  • Author(s): Yutaka Inagaki
  • Journal Title: Hepatol Res Volume: 42 Issue: 6 Pages: 543-548
  • DOI: 10.1111/j.1872-034x.2012.00978.x
  • NAID: 10031144268
  • Peer Reviewed
• [Journal Article] Novel strategies for hepatocellular carcinoma based on MMPs science. (2012)
  • Author(s): Isao Okazaki
  • Journal Title: Anti-Cancer Agents Med Chem Volume: 12 Pages: 753-763
  • Peer Reviewed
• [Journal Article] 肝線維症治療の研究はどこまで進展したか？ (2012)
  • Author(s): 稲垣 豊
  • Journal Title: 肝胆膵 Volume: 65 Pages: 253-260
• [Journal Article] Novel anti-fibrotic modalities for liver fibrosis : Molecular targeting and regenerative medicine in fibrosis therapy (2012)
  • Author(s): Yutaka Inagaki
  • Journal Title: J Gastroenterol Hepatol Volume: 27 Issue: s2 Pages: 85-88
  • DOI: 10.1111/j.1440-1746.2011.07006.x
• [Journal Article] Differential contribution of dermal resident and bone marrow-derived cells to collagen production during wound healing and fibrogenesis in mice (2011)
  • Author(s): Higashiyama R, Nakao S, Inagaki Y, et al
  • Journal Title: J Invest Dermatol Volume: 131 Pages: 529-536
  • Peer Reviewed
• [Journal Article] A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice (2011)
  • Author(s): Higashi K, Tomigahara Y, Inagaki Y, et al
  • Journal Title: J Biol Chem Volume: 286 Pages: 4485-4492
  • Peer Reviewed
• [Journal Article] Methodological development of a clonogenic assay to determine endothelial progenitor cell potential (2011)
  • Author(s): Masuda H, Alev C, Asahara T, et al
  • Journal Title: irc Res Volume: 109 Pages: 20-37
  • Peer Reviewed
• [Journal Article] Concise review: Circulating endothelial progenitor cells for vascular medicine (2011)
  • Author(s): Asahara T, Kawamoto A, Masuda H
  • Journal Title: Stem Cells Volume: 29 Pages: 1650-1655
  • Peer Reviewed
• [Journal Article] 創傷治癒ならびに皮膚線維化過程における骨髄由来細胞の役割 (2011)
  • Author(s): 稲垣豊
  • Journal Title: 日本皮膚科学会雑誌 Volume: 121 Pages: 3185-3187
  • NAID: 10031165157
• [Journal Article] A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice. (2011)
  • Author(s): Kiyoshi Higashi
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 4485-4492
  • Peer Reviewed
• [Journal Article] Differential contribution of dermal resident and bone marrow-derived cells to collagen production during wound healing and fibrogenesis in mice. (2011)
  • Author(s): Reiichi Higashiyama
  • Journal Title: Journal of Investigative Dermatology Volume: 131 Pages: 529-536
  • Peer Reviewed
• [Journal Article] Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice (2010)
  • Author(s): Ii M, Takeshita K, Asahara T, et al
  • Journal Title: Circulation Volume: 121 Pages: 1104-1112
  • Peer Reviewed
• [Journal Article] TGF-β/Smadシグナルを標的とした肝線維症の治療戦略 (2010)
  • Author(s): 稲垣豊
  • Journal Title: 瘢痕・ケロイド治療ジャーナル Volume: 4 Pages: 35-39
• [Journal Article] 臓器線維症の病態と治療戦略 (2010)
  • Author(s): 稲垣豊
  • Journal Title: 十全医学会雑誌 Volume: 119 Pages: 56-57
  • NAID: 10027445155
• [Presentation] Identification of a novel bone marrow cell-derived factor that suppresses fibrogenesis and accelerates regeneration of murine fibrotic liver (2012)
  • Author(s): Inagaki Y, Sumiyoshi H, Fukumitsu H, et al
  • Organizer: 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston,MA,U.S.A
  • Year and Date: 2012-11-12
• [Presentation] 線維肝の再生における骨髄と肝臓の臓器相関 (2012)
  • Author(s): 稲垣 豊
  • Organizer: 第11回日本再生医療学会総会、シンポジウム5「臓器再生の名脇役達-血管再生と炎症・間質組織の生理学的および病理学的役割-」
  • Place of Presentation: 横浜
  • Year and Date: 2012-06-14
• [Presentation] Notch/Jagged-1シグナルを介した肝前駆細胞動員と線維化の制御機構 (2012)
  • Author(s): 三上健一郎、東山礼一、稲垣 豊、他
  • Organizer: 第48回肝臓学会総会、ワークショップ21「肝線維化の病態解明と治療への展開」
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-08
• [Presentation] 骨髄細胞に由来する新たな肝線維化改善・再生促進因子の同定と臨床応用 (2012)
  • Author(s): 福光 寛、東山礼一、稲垣 豊、他
  • Organizer: 第48回肝臓学会総会、ワークショップ15「肝再生、幹細胞研究が臨床医学にもたらす可能性」
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-07
• [Presentation] 骨髄造血幹細胞ならびに間葉系幹細胞による肝線維化の病態形成 (2011)
  • Author(s): 中尾祥絵
  • Organizer: 第25回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 東京ガーデンパレス(東京)
  • Year and Date: 2011-12-18
• [Presentation] 骨髄細胞に由来する新たな肝線維化改善・再生促進因子の同定と臨床応用 (2011)
  • Author(s): 福光寛
  • Organizer: 第25回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 東京ガーデンパレス(東京)
  • Year and Date: 2011-12-18
• [Presentation] 肝細胞増殖因子HGFが有する肝癌細胞増殖抑制作用の解析 (2011)
  • Author(s): 瀧澤友里
  • Organizer: 第25回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 東京ガーデンパレス(東京)
  • Year and Date: 2011-12-18
• [Presentation] Notch/Jagged-1 signal modulates pathophysiological correlation between fibrogenesis and regeneration in murine liver (2011)
  • Author(s): Mikami K, Nakao S, Inagaki Y, et al
  • Organizer: 62nd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA, U.S.A
  • Year and Date: 2011-11-07
• [Presentation] Notch/Jagged-1 signal modulates pathophysiological correlation between fibrogenesis and regeneration in murine liver (2011)
  • Author(s): Kenichiro Mikami
  • Organizer: 62th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West (San Francisco, CA)
  • Year and Date: 2011-11-07
• [Presentation] Anti-fibrotic modalities for liver fibrosis (2011)
  • Author(s): Yutaka Inagaki
  • Organizer: 6th International Symposium on ALPD and Cirrhosis
  • Place of Presentation: Fukuoka Convention Center (Fukuoka, Japan)(招待講演)
  • Year and Date: 2011-10-21
• [Presentation] 肝線維化と肝再生の病態連繋におけるNotch/Jagged-1シグナルの関与 (2011)
  • Author(s): 三上健一郎
  • Organizer: 第18回肝細胞研究会
  • Place of Presentation: 東京ガーデンパレス(東京)
  • Year and Date: 2011-06-24
• [Presentation] 酸化ストレスに起因する肝細胞傷害と肝線維化進展の高感度検出系の確立 (2011)
  • Author(s): 皆川香織
  • Organizer: 第43回日本結合組織学会学術大会第58回マトリックス研究会大会合同学術集会
  • Place of Presentation: 別府ビーコンプラザ(大分)
  • Year and Date: 2011-06-11
• [Presentation] 骨髄造血幹細胞ならびに間葉系幹細胞による肝線維症の病態形成 (2011)
  • Author(s): 中尾祥絵
  • Organizer: 第43回日本結合組織学会学術大会第58回マトリックス研究会大会合同学術集会
  • Place of Presentation: 別府ビーコンプラザ(大分)
  • Year and Date: 2011-06-11
• [Presentation] Pathogenesis of hepatic fibrosis, update (2011)
  • Author(s): Yutaka Inagaki
  • Organizer: 17th Annual Meeting of the Korean Association for the Study of the Liver
  • Place of Presentation: Sheraton Grande Walkerhill Hotel (Seoul, Korea)(招待講演)
  • Year and Date: 2011-06-10
• [Presentation] 肝線維化と肝再生の病態連繋におけるNotch/Jagged-1シグナルの関与 (2011)
  • Author(s): 三上健一郎、東山礼一、稲垣 豊
  • Organizer: 第47回日本肝臓学会総会、ワークショップ 10「肝再生医学研究の新展開」
  • Place of Presentation: 東京
  • Year and Date: 2011-06-03
• [Presentation] 肝線維化と肝再生の病態連繋におけるNotch/Tagged-1シグナルの関与 (2011)
  • Author(s): 三上健一郎
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: ホテルグランパシフィックLE DAIBA(東京)
  • Year and Date: 2011-06-03
• [Presentation] Notch/Jagged-1 signal modulates pathophysiological correlation between fibrogenesis and regeneration in murineliver (2011)
  • Author(s): Mikami K, Nakao S, Inagaki Y
  • Organizer: American Association for the Study of Liver Diseases, Basic Research Single Topic Conference"Stem Cells in Liver Diseases and Cancer"
  • Place of Presentation: Atlanta, GA, U.S.A.
  • Year and Date: 2011-03-19
• [Presentation] Notch/Jagged-1 signal modulates pathophysiological correlation between fibrogenesis and regeneration in murine liver. (2011)
  • Author(s): Yutaka Inagaki
  • Organizer: American Association for the Study of Liver Diseases, Basic Research Single Topic Conference "Stem Cells in Liver Diseases and Cancer"
  • Place of Presentation: Atlanta, GA
  • Year and Date: 2011-03-19
• [Presentation] Jagged-1を介した肝線維化と再生の病態連繋 (2011)
  • Author(s): 三上健一郎
  • Organizer: 第10回日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-03-01
• [Presentation] 胆汁うっ滞型肝線維症におけるコラーゲン産生細胞の起源と初期動態 (2010)
  • Author(s): 茂呂忠
  • Organizer: 第24回肝類洞壁細胞研究会学術大会
  • Place of Presentation: 福島
  • Year and Date: 2010-11-27
• [Presentation] Molecular mechanisms of hepatic stellate cell activation. (2010)
  • Author(s): Yutaka Inagaki
  • Organizer: 9th Japan Society of Hepatology Single Topic Conference "NASH 2010"
  • Place of Presentation: Tokyo, Japan.
  • Year and Date: 2010-11-19
• [Presentation] Jagged-1を介した肝線維化と再生の病態連繋 (2010)
  • Author(s): 三上健一郎
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-14
• [Presentation] Notch/Jagged-1 signal modulates pathophysiological correlation between fibrogenesis and regeneration in murine liver. (2010)
  • Author(s): Kenichiro Mikami
  • Organizer: 1st Japanese Society of Gastroenterology International Topic Conference : Stem Cells in Digestive Organs
  • Place of Presentation: Kamakura, Japan
  • Year and Date: 2010-09-25
• [Presentation] Matrix metalloproteinase (MMP)-13 enhances migration of bone marrow-derived cells and contributes to the repair of experimental liver fibrosis. (2010)
  • Author(s): Reiichi Higashiyama
  • Organizer: 15th International Symposium on Cells of the Hepatic Sinusoid
  • Place of Presentation: Pasadena, CA
  • Year and Date: 2010-08-31
• [Presentation] マウス胆汁うっ滞型肝線維症に胆管上皮細胞の上皮間葉移行は関与するか (2010)
  • Author(s): 茂呂忠
  • Organizer: 第42回日本結合組織学会学術大会・第57回マトリックス研究会大会合同学術集会
  • Place of Presentation: 秋田
  • Year and Date: 2010-08-19
• [Presentation] Jagged-1を介した肝線維化と再生の病態連繋 (2010)
  • Author(s): 三上健一郎
  • Organizer: 第42回日本結合組織学会学術大会・第57回マトリックス研究会大会合同学術集会
  • Place of Presentation: 秋田
  • Year and Date: 2010-08-19
• [Presentation] 皮膚創傷治癒ならびに線維化過程における骨髄由来細胞のコラーゲン合成への関与の相違 (2010)
  • Author(s): 中尾祥絵
  • Organizer: 第42回日本結合組織学会学術大会・第57回マトリックス研究会大会合同学術集会
  • Place of Presentation: 秋田
  • Year and Date: 2010-08-19
• [Presentation] 肝線維化と再生の病態連繋における骨髄と末梢の臓器相 (2010)
  • Author(s): 稲垣 豊、東山礼一、三上健一郎
  • Organizer: 第17回肝細胞研究会、シンポジウム2「肝幹細胞と肝再生」
  • Place of Presentation: 秋田
  • Year and Date: 2010-06-19
• [Presentation] 肝線維化と再生の病態連繋における骨髄と末梢の臓器相関 (2010)
  • Author(s): 稲垣豊
  • Organizer: 第17回肝細胞研究会
  • Place of Presentation: 秋田
  • Year and Date: 2010-06-19
• [Presentation] Matrix metalloproteinase (MMP)-13による線維化改善と類洞構造の修復を介した肝再生治療戦略 (2010)
  • Author(s): 東山礼一
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形
  • Year and Date: 2010-05-28
• [Presentation] 骨髄細胞に由来する新たな肝線維化改善・再生促進因子の同定と臨床応用．
  • Author(s): 福光 寛
  • Organizer: 第48回肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] 胆汁うっ滞型肝線維症におけるコラーゲン産生細胞の起源と初期動態．
  • Author(s): 茂呂 忠
  • Organizer: 第48回肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] Notch/Jagged-1シグナルを介した肝前駆細胞動員と線維化の制御機構．
  • Author(s): 三上健一郎
  • Organizer: 第48回肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] 骨髄細胞に由来する新たな肝線維化改善・再生促進因子の同定と臨床応用．
  • Author(s): 住吉秀明
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: 横浜
• [Presentation] 線維肝の再生における骨髄と肝臓の臓器相関．
  • Author(s): 稲垣 豊
  • Organizer: 第11回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] Hepatocyte growth factor (HGF)による細胞増殖制御機構の解明．
  • Author(s): 瀧澤友里
  • Organizer: 第19回肝細胞研究会
  • Place of Presentation: 札幌
• [Presentation] Identification of a novel bone marrow cell-derived factor that suppresses fibrogenesis and accelerates regeneration of murine fibrotic liver.
  • Author(s): Yutaka Inagaki
  • Organizer: 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] 胆汁うっ滞型肝線維症におけるコラーゲン産生細胞の起源と初期動態．
  • Author(s): 茂呂 忠
  • Organizer: 第26回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 宇部
• [Presentation] 細胞種特異的Notchシグナルによる肝線維化と再生の病態連繋．
  • Author(s): 瀧澤友里
  • Organizer: 第26回肝類洞壁細胞研究会学術集会
  • Place of Presentation: 宇部
• [Presentation] 細胞系譜特異的Notch/Jagged-1シグナルによる肝線維化と再生の病態形成．
  • Author(s): 住吉秀明
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
• [Book] 肝線維化病態に対する分子形態学的アプローチ.病気の分子形態学 (2011)
  • Author(s): 日本臨床分子形態学会編
  • Publisher: 学際企画
• [Book] 肝線維化病態に対する分子形態学的アプローチ.病気の分子形態学(日本臨床分子形態学会編) (2011)
  • Author(s): 稲垣豊
  • Publisher: 学際企画
• [Remarks]
  • URL: http://www.med.u-tokai.ac.jp/daigakuin/pdf/inagaki_yutaka_2013_04_01.pdf
• [Remarks] 東海大学大学院医学研究科研究指導教員一覧
  • URL: http://www.med.u-tokai.ac.jp/daigakuin/pdf/inagaki_yutaka_2013_04_01.pdf
• [Remarks]
  • URL: http://www.med.u-tokai.ac.jp/daigakuin/pdf/inagaki.pdf
• [Patent(Industrial Property Rights)] 肝臓線維化抑制剤 (2011)
  • Inventor(s): 稲垣 豊、茂呂 忠
  • Industrial Property Rights Holder: 学校法人東海大学・株式会社ミノファーゲン製薬
  • Filing Date: 2011-11-16
• [Patent(Industrial Property Rights)] 生体組織再生を促進させる薬剤を製造するための加工細胞 (2011)
  • Inventor(s): 稲垣 豊、東山礼一、東 清史、斎藤幸一
  • Industrial Property Rights Holder: 学校法人東海大学・住友化学株式会社
  • Filing Date: 2011-05-24
• [Patent(Industrial Property Rights)] 肝臓線維化抑制剤 (2011)
  • Inventor(s): 稲垣豊, 茂呂忠
  • Industrial Property Rights Holder: 学校法人東海大学、株式会社ミノファーゲン製薬
  • Industrial Property Number: 2011-250746
  • Filing Date: 2011-11-16
• [Patent(Industrial Property Rights)] 生体組織再生を促進させる薬剤を製造するための加工細胞 (2010)
  • Inventor(s): 稲垣 豊、東山礼一、東 清史、斎藤幸一
  • Industrial Property Rights Holder: 学校法人東海大学・住友化学株式会社
  • Filing Date: 2010-05-28