Analysis of cell-to-cell interaction between hepatic progenitor cells and hepatic mesenchymal cells and a search of target molecules for a therapy of liver fibrosis

• Project/Area Number: 18K07964
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: AZUMA Seishin 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 (10376783)
• 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, 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 細胞間相互作用 / 肝星細胞 / 胆管細胞 / ヒトiPS細胞 / 肝幹/前駆細胞 / 肝前駆細胞 / 間葉系細胞 / iPS細胞 / 分化

Outline of Final Research Achievements

The aim of this research project is to establish a novel co-culture system of murine hepatic progenitor cells (HPCs) and murine liver mesenchymal cells (LMCs) and to clarify the cell-to-cell interaction between HPCs and LMCs. Our data revealed that murine LMCs secret vasoactive intestinal peptide (VIP). VIP signaling significantly encouraged cholangiocytic organoid formation derived from HPCs and upregulated the formation of tight junction protein in vitro. Administration of VIP to liver-injured mice promoted the restoration of damaged tight junctions in bile ducts in vivo. Human iPS-derived LMCs and VIP also promoted the formation of cholangiocytic organoids derived from human iPS-derived LPCs. Our studies suggest that VIP-related signaling is a therapeutic target for restoration of damaged liver tissue.

Academic Significance and Societal Importance of the Research Achievements

近年、肝細胞と胆管細胞、そして間葉系細胞との3者の細胞間相互作用を制御しうる分子標的を探索し、肝疾患の検査・治療へ応用する試みが注目を集めている。本研究では、主として肝前駆細胞の分化と胆管形成に肝間葉系細胞が与える影響について詳細に解析を行った。
我々が解明したVIPに関しての前述の機能は、これまで全く未知の知見であり、米国肝臓病学会の機関誌に掲載され、種々の学会で主題として発表するなど、研究の新規性が学術的に高く評価されている。同様に、肝疾患の標的因子として、VIPのような神経ペプチドの機能にはこれまで不明の点が多く、今後の肝疾患治療への応用性の見地からも、社会的な意義が深いと考えられる。

Research Products

• [Int'l Joint Research] Stanford University School of Medicine(米国)
• [Journal Article] Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis (2021)
  • Author(s): Sapena V, Enea M, Torres F, Celsa C, Rios J, Rizzo GEM, Nahon P, Marino Z, Tateishi R, Minami T, Sangiovanni A, Forns X, Toyoda H, Brillanti S, Conti F, Degasperi E, Yu ML, Tsai PC, Jean K, El Kassas M, Shousha HI, Omar A, Zavaglia C, Nagata H, Nakagawa M, Asahina Y, et al
  • Journal Title: Gut Volume: in press Issue: 3 Pages: 323663-323663
  • DOI: 10.1136/gutjnl-2020-323663
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal. (2021)
  • Author(s): Ryo Morikawa, Yasuhiro Nemoto, Yuki Yonemoto, Shohei Tanaka, Yuria Takei, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Kengo Nozaki , Tomohiro Mizutani, Tetsuya Nakamura, Mamoru Watanabe, Ryuichi Okamoto.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 11 Issue: 5 Pages: 1483-1503
  • DOI: 10.1016/j.jcmgh.2021.01.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mac-2 binding protein glycosylation isomer as a novel predictive biomarker for patient survival after hepatitis C virus eradication by DAAs (2020)
  • Author(s): Nakagawa M, Nawa N, Takeichi E, Shimizu T, Tsuchiya J, Sato A, Miyoshi M, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Fujiwara T, Watanabe M, Tanaka Y, Asahina Y; Ochanomizu Liver Conference Study Group.
  • Journal Title: Journal of Gastroenterology Volume: 55 Issue: 10 Pages: 990-999
  • DOI: 10.1007/s00535-020-01715-6
  • Peer Reviewed / Open Access
• [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] Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma (2020)
  • Author(s): Kirino S, Tsuchiya K, Kurosaki M, Kaneko S, Inada K, Yamashita K, Osawa L, Hayakawa Y, Sekiguchi S, Okada M, Wang W, Higuchi M, Takaura K, Maeyashiki C, Tamaki N, Yasui Y, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Izumi N.
  • Journal Title: PLoS One Volume: 15 Issue: 4 Pages: e0231828-e0231828
  • DOI: 10.1371/journal.pone.0231828
  • Peer Reviewed / Open Access
• [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] 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] 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] 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] 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] 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] 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] .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
• [Presentation] ヒトiPS細胞由来肝臓構成細胞による肝線維症の病態解析 (2021)
  • Author(s): 柿沼 晴、三好正人、紙谷聡英、土屋淳、志水太郎、新田沙由梨、村川美也子、北畑富貴子、東正新、中川美奈、朝比奈靖浩、岡本隆一.
  • Organizer: 第20回日本再生医療学会総会
  • Invited
• [Presentation] Comprehensive analysis of cancer-related genes and AAV/hepatitis B virus integration into genome on development of hepatocellular carcinoma in patients with prior hepatitis B virus infection. (2020)
  • Author(s): Fukiko Kawai-Kitahata, Yasuhiro Asahina , Sei Kakinuma, Miyako Murakawa, Sayuri Nitta, Masato Miyoshi, Ayako Sato, Jun Tsuchiya, Taro Shimizu, Eiko Takeichi, Mina Nakagawa, Yasuhiro Itsui, Seishin Azuma, Shinji Tanaka , Minoru Tanabe, Shinya Maekawa, Nobuyuki Enomoto and Mamoru Watanabe.
  • Organizer: EASL The Digital International Liver Congress 2020
  • Int'l Joint Research
• [Presentation] Poor improvement of on-treatment FIB-4 index after initiation of nucleos(t)ide analogs is associated with development of hepatocellular carcinoma in both cirrhotic and non-cirrhotic chronic hepatitis B patients. (2020)
  • Author(s): Miyako Murakawa, Taro Shimizu, Eiko Takeichi, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Fukiko Kawai-Kitahata, Sayuri Nitta, Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma, Yasuhiro Asahina.
  • Organizer: EASL The Digital International Liver Congress 2020
  • Int'l Joint Research
• [Presentation] Vasoactive intestinal peptideの肝内胆管形成および胆汁うっ滞性肝障害への寄与. (2020)
  • Author(s): 佐藤綾子、柿沼 晴、志水太郎、土屋 淳、三好正人、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.
  • Organizer: 第24回日本肝臓学会大会
• [Presentation] 肝間葉系細胞によるvasoactive intestinal peptideを介した胆管形成調節機構. (2020)
  • Author(s): 柿沼 晴、佐藤綾子、三好正人、紙谷聡英、土屋 淳、志水太郎、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27回肝細胞研究会
• [Presentation] 肝間葉系細胞由来vasoactive intestinal peptideによる胆管形成の促進機構 (2020)
  • Author(s): 佐藤綾子、柿沼 晴、朝比奈靖浩.
  • Organizer: 第56回日本肝臓学会総会
• [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] 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] 背景肝の線維化からみた肝細胞がんにおけるがん関連遺伝子変異と viral integration の解析. (2019)
  • Author(s): 北畑富貴子、朝比奈靖浩、村川美也子、新田沙由梨、柿沼 晴、角田知之、三好正人、四宮恵美、佐藤綾子、土屋 淳、井津井康浩、中川美奈、東 正新、田中真二、田邉 稔、前川伸哉、榎本信幸、渡辺 守.
  • Organizer: 第55回日本肝臓学会総会
• [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: The 70th Annual Meeting of the American Association for the Study of Liver Disease
  • Int'l Joint Research
• [Presentation] ヒト iPS 細胞による疾患モデルを利用した先天性肝線維症分子標的の探索 (2019)
  • Author(s): 柿沼 晴、角田 知之、三好 正人、紙谷 聡英、佐藤 綾子、土屋 淳、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: JDDW2019
• [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、東 正新、三好正人、角田知之、金子 俊、井津井康浩、朝比奈靖浩、渡辺 守
  • Organizer: 第25回肝細胞研究会
• [Presentation] NAFLD における肝細胞癌リスク因子についての検討 (2018)
  • Author(s): 東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第54回日本肝癌研究会
• [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、東 正新、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、朝比奈靖浩、渡辺 守.
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] NAFLD由来の肝細胞癌に関連したリスク因子の検討 (2018)
  • Author(s): 東 正新、朝比奈靖浩、三好正人、井上恵美、角田知之、佐藤綾子、金子 俊、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、柿沼 晴、渡辺 守
  • Organizer: JDDW2019
• [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