Study on functions of Matrix Metalloproteinase-related molecules in progressive fibrogenesis in chronic liver diseases

• Project/Area Number: 17K09407
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Itsui Yasuhiro 東京医科歯科大学, 医学部附属病院, 講師 (20401341)
• Co-Investigator(Kenkyū-buntansha): 柿沼 晴 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (30372444) ; 朝比奈 靖浩 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692) ; 渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝線維化 / 非アルコール性脂肪性肝炎 / 発生・分化 / 肝前駆細胞 / 細胞間相互作用 / 肝星細胞 / 肝臓病学 / 再生医学 / iPS細胞 / Matrix Metalloproteinase / 脂肪性肝炎

Outline of Final Research Achievements

Functions of Matrix Metalloproteinase (MMP)-2 and MMP-14 in liver fibrosis are not fully elucidated. The aims of this research project are to clarify the function of MMP-2 in progression of liver fibrosis and to elucidate the molecular mechanism of the function of MMP-14 in hepatic stellate cells. Our data showed that loss of systemic MMP-2 function exacerbates the liver fibrosis in a mouse steatohepatitis model. Moreover, loss of MMP-14 suppressed the production of vasoactive intestinal peptide (VIP) in mesenchymal cells of perinatal livers. VIP facilitates reconstitution of tight junction of cholangiocytes, and contributes to recovery from cholestatic liver injury in mice.

Academic Significance and Societal Importance of the Research Achievements

Matrix Metalloproteinase (MMP) は、最も主要な細胞外基質分解酵素であり、中でもMMP-2とMMP-14は炎症・再生の様々な過程に深く関与することが知られているが、肝線維化や肝障害における機能的意義には不明点が残されている。
本研究ではMMP-2欠損が脂肪性肝炎の線維形成に抑制的な機能を有することを初めて示した。同様にMMP-14とVIPの関係性を初めて示し、肝臓間葉系細胞から分泌されるVIPが胆管上皮細胞におけるtight junctionの構築を促進することを初めて明らかにした。これらの知見は慢性肝疾患の肝線維化を改善しうる新規治療の開発に貢献するものである。

Research Products

• [Journal Article] Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts (2020)
  • Author(s): Sato A, Kakinuma S, Miyoshi M, Kamiya A, Tsunoda T, Kaneko S, Tsuchiya J, Shimizu T, Takeichi E, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Koshikawa N, Seiki S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Hepatology Communications Volume: 4 Issue: 2 Pages: 235-254
  • DOI: 10.1002/hep4.1459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Time course alterations of virus sequences and immunoglobulin titers in a chronic hepatitis E patient (2020)
  • Author(s): Nitta Sayuri、Takahashi Kazuaki、Kawai‐Kitahata Fukiko、Tsuchiya Jun、Sato Ayako、Miyoshi Masato、Murakawa Miyako、Itsui Yasuhiro、Nakagawa Mina、Azuma Seishin、Kakinuma Sei、Watanabe Mamoru、Asahina Yasuhiro
  • Journal Title: Hepatology Research Volume: 50 Issue: 4 Pages: 524-531
  • DOI: 10.1111/hepr.13480
  • Peer Reviewed
• [Journal Article] Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma‐like area and metachronous hepatocellular carcinoma (2019)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kaneko S, Tsuchiya J, Sato A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Tanabe M, Sugawara E, Takemoto A, Ojima H, Sakamoto M, Muraoka M, Takano S, Maekawa S, Enomoto N and Watanabe M.
  • Journal Title: Hepatology Research Volume: 49 Issue: 12 Pages: 1466-1474
  • DOI: 10.1111/hepr.13403
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Fibrocystin Promotes Interleukin-8-Dependent Proliferation and CTGF Production of Biliary Epithelium. (2019)
  • Author(s): Tsunoda T, Kakinuma S, Miyoshi M, Kamiya A, Kaneko S, Sato A, Tsuchiya J, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Sogo T, Komatsu H, Mukouchi R, Inui A, Fujisawa T, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Journal of Heptatology Volume: 印刷中 Issue: 1 Pages: 143-152
  • DOI: 10.1016/j.jhep.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combinations of two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents are effective for hepatitis C virus with NS5A-P32 deletion in humanized-liver mice (2019)
  • Author(s): Doi Akira、Hikita Hayato、Kai Yugo、Tahata Yuki、Saito Yoshinobu、Nakabori Tasuku、Yamada Ryoko、Kodama Takahiro、Sakamori Ryotaro、Murayama Asako、Nitta Sayuri、Asahina Yasuhiro、Suemizu Hiroshi、Tatsumi Tomohide、Kato Takanobu、Takehara Tetsuo
  • Journal Title: Journal of Gastroenterology Volume: 54 Issue: 5 Pages: 449-458
  • DOI: 10.1007/s00535-018-01541-x
  • Peer Reviewed
• [Journal Article] Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells (2019)
  • Author(s): Kakinuma S and Watanabe M
  • Journal Title: Immunological Medicine Volume: 42 Issue: 2 Pages: 71-78
  • DOI: 10.1080/25785826.2019.1657254
  • Peer Reviewed / Open Access
• [Journal Article] Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients (2019)
  • Author(s): Nitta S, Asahina Y, Kato T, Tsuchiya J, Inoue-Shinomiya E, Sato A, Tsunoda T, Miyoshi M, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Hikita H, Takehara T, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5722-5722
  • DOI: 10.1038/s41598-019-42114-z
  • Peer Reviewed / Open Access
• [Journal Article] LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. (2019)
  • Author(s): Miyoshi M, Kakinuma S, Kamiya A, Tsunoda T, Tsuchiya J, Sato A, Kaneko S, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2072-2072
  • DOI: 10.1038/s41598-018-37430-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diabetic Retinopathy as a Risk Factor Associated with the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. (2019)
  • Author(s): Azuma S, Asahina Y, Kakinuma S, Azuma K, Miyoshi M, Inoue E, Tsunoda T, Sato A, Kaneko S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Tomita M, Nakagawa M, Watanabe M.
  • Journal Title: Digestive Diseases Volume: 37 Issue: 3 Pages: 247-254
  • DOI: 10.1159/000493580
  • Peer Reviewed
• [Journal Article] .Association of serum IFN-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Emi Inoue-Shinomiya, Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Sayuri Nitta, Fukiko Kawai-Kitahata, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kazumoto Murata, Masashi Mizokami, Mamoru Watanabe.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 500-511
  • DOI: 10.1111/hepr.13307
  • Peer Reviewed / Open Access
• [Journal Article] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. (2017)
  • Author(s): Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M
  • Journal Title: J Hepatol Volume: 67 Issue: 5 Pages: 933-939
  • DOI: 10.1016/j.jhep.2017.05.028
  • Peer Reviewed / Open Access
• [Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin. (2017)
  • Author(s): Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1212-1218
  • DOI: 10.1111/hepr.12867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic IFNL4 expression is associated with non-response to interferonbased therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients. (2017)
  • Author(s): Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano Y, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda S, Watanabe M.
  • Journal Title: J Med Virol Volume: in press Issue: 7 Pages: 1241-1247
  • DOI: 10.1002/jmv.24763
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The association of serum IFN-λ3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Murakawa M, Inoue-Shinomiya E, Asahina Y, Nakagawa M, Tsuchiya J, Sato A, Miyoshi M, Tsunoda T, Kawai-Kitahata F, Nitta S, Itsui Y, Kakinuma S, Azuma S, Watanabe M.
  • Organizer: The 54th annual meeting of the European association for the study of the liver
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞疾患モデルを利用した先天性肝線維症における病態と分子標的の解明. (2019)
  • Author(s): 角田知之、柿沼 晴、三好正人、紙谷聡英、佐藤綾子、土屋 淳、金子 俊、四宮恵美、北畑富貴子、村川美也子、新田沙由梨、井津井康浩、中川美奈、東 正新、朝比奈靖浩、渡辺 守.
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] Vasoactive intestinal peptide による胆管形成調節の分子機序. (2019)
  • Author(s): 佐藤綾子、柿沼 晴、土屋 淳、三好正人、角田知之、井津井康浩、中川美奈、東 正新、朝比奈靖浩、渡辺 守.
  • Organizer: 第26回肝細胞研究会
• [Presentation] 細胆管細胞がん内の異なる表現型及び肝細胞がんにおけるがん関連遺伝子の網羅的解析. (2019)
  • Author(s): 北畑富貴子、朝比奈靖浩、金子 俊、村川美也子、新田沙由梨、柿沼 晴、三好正人、佐藤綾子、井津井康浩、中川美奈、東 正新、田邉 稔、菅原江美子、竹本 暁、坂元亨宇、尾島英知、村岡 優、前川伸哉、榎本信幸、渡辺 守.
  • Organizer: 第55回日本肝癌研究会
• [Presentation] Comprehensive analysis of cancer gene mutations and viral integration in hepatocellular carcinoma arising from non-fibrotic liver. (2019)
  • Author(s): Asahina Y, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Azuma S, Kakinuma S.
  • Organizer: AASLD The Liver Meeting 2019
  • Int'l Joint Research
• [Presentation] Difference of gene mutational profile among viral- and non-viral HCC with or without prior HBV infection: Results of comprehensive deep sequencing analyses of cancer genes and HBV/AAV integration (2018)
  • Author(s): Kitahata-kawai F, Asahina Y, KakinumaS, Murakawa M, Nitta S, Nagata H, Kaneko S, Inoue E, Miyoshi M, Tsunoda T, Sato A, Nakagawa M, Itsui Y, Azuma S, Tanaka S, Tanabe M, Maekawa S, Enomoto N and Watanabe M.
  • Organizer: EASL The International Liver Congress 2018
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来星細胞様細胞における転写因子LHX2 の機能解析 (2018)
  • Author(s): 三好正人、柿沼 晴、金子俊、紙谷聡英、佐藤綾子、角田知之、四宮恵美、北畑富貴子、新田沙由梨、村川美也子、井津井康浩、中川美奈、東正新、朝比奈靖浩、渡辺 守.
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 肝前駆細胞による胆管形成に対する胎生期肝間葉系細胞との細胞間相互作用 (2018)
  • Author(s): 佐藤綾子、柿沼 晴、三好正人、角田知之、金子 俊、井津井康浩、東 正新、朝比奈靖浩、渡辺 守.
  • Organizer: 第25回肝細胞研究会
• [Presentation] Post-Treatment M2BPGi Level Is Useful for Predicting HCC Occurrence and Recurrence after Viral Eradication in Chronic Hepatitis C Patients. (2018)
  • Author(s): Nakagawa M, Asahina Y, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tomita M, Watanabe M.
  • Organizer: AASLD The Liver Meeting 2018
  • Int'l Joint Research
• [Presentation] 免疫抑制状態によるE型肝炎慢性化症例の解析 (2018)
  • Author(s): 井津井康浩、北畑富貴子、新田沙由梨、村川美也子、中川美奈、東 正新、柿沼 晴、朝比奈靖浩、渡辺 守.
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] 免疫抑制状態でのE 型肝炎慢性化症例の解析 (2017)
  • Author(s): 井津井康浩、大谷賢志、北畑富貴子、新田沙由梨、村川美也子、中川美奈、柿沼 晴、東 正新、高橋和明、 朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 食餌誘導性NASH モデル マウスにおけるMatrix Metalloporoteinase-2 の機能的解析 (2017)
  • Author(s): 柿沼 晴、浅野 侑、三好正人、佐藤綾子、角田知之、金子 俊、大谷賢志、永田紘子、北畑富貴子、村川 美也子、新田沙由梨、井津井康浩、中川美奈、東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] LHX2 発現によるヒトiPS 由来間葉系細胞の機能調節 (2017)
  • Author(s): 三好正人、柿沼 晴、紙谷聡英、金子 俊、角田知之、佐藤綾子、浅野 侑、井津井康浩、東 正新、朝比 奈靖浩、渡辺 守
  • Organizer: 第24回肝細胞研究会
• [Presentation] 肝炎ウイルス制御下およびB 型肝炎ウイルス既往感染における肝細胞癌遺伝子変異の検討 (2017)
  • Author(s): 北畑富貴子、朝比奈靖浩、田中信二、村川美也子、新田沙由梨、柿沼 晴、永田紘子、金子 俊、浅野 侑、 角田知之、三好正人、井上恵美、佐藤綾子、井津井康浩、中川美奈、東 正新、田邉 稔、前川伸哉、榎本 信幸、渡辺 守
  • Organizer: 第53回日本肝癌研究会
• [Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with All-Oral DAAs -propensity score-matched analysis of a prospective database (2017)
  • Author(s): Nakagawa M, Asahina Y, Nagata H, Kaneko S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Watanabe M
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] A novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses (2017)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Nitta S, Sato A, Asano Y, Nagata H, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Book] A Rodent Model for Cell Transplantation of Hepatic Progenitor Cells (Hepatic Stem Cells) (2019)
  • Author(s): Kakinuma S and Kamiya A (In: Tanimizu N)
  • Total Pages: 248
  • Publisher: Springer Nature
  • ISBN: 9781493989614