Examination of liver fibrosis and hepatocarcinogenesis by using human iPS cell-derived hepatic stellate cells

• Project/Area Number: 19K08415
• 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: Nakagawa Mina 東京医科歯科大学, 統合教育機構, 准教授 (30401342)
• 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)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヒトiPS細胞 / 肝星細胞 / M2BPGi / 肝細胞癌 / SVR / WFA-positive M2BP / iPS細胞 / 肝線維化 / 肝発癌機構

Outline of Research at the Start

研究グループのこれまでの解析によって、実際の臨床データから抽出された因子に関して検討を行うため、我々が独自に樹立したiPS細胞分化誘導法の学術・技術基盤をもとに、肝線維化、肝発癌機構の解明を目指して、以下の3つのテーマで基礎・臨床融合研究を行う。
1)iPS細胞培養系を用いた肝疾患病態モデルを用いた肝星細胞の分化誘導法の確立と誘導効率化の検討　2)iPS由来間葉系細胞を用いたin vitro解析による線維化関連因子の分子生物学的意義の検討　3) M2BPGiの動態と臨床的意義の解析
本研究では基礎と臨床の両面からアプローチすることでウイルス制御下での肝線維化、発癌機構の解明を目指す。

Outline of Final Research Achievements

In this study, we have established a co-culture system of iPS-derived hepatic stellate cells (iPS-HSCs) and human hepatocyte organoids originally, and by using these system, the concentration of M2BPGi (WFA-positive M2BP) in the supernatant increased, which revealed that we could apply these system to a chronic inflammation analysis model. A prospective, multicenter and observational study using the database of patients after HCV eradication by direct-acting antiviral agents (DAAs) to evaluate the patients’ survival after a sustained virological response (SVR). M2BPGi at SVR is a potential predictor for patients’ survival and a candidate biomarker for detecting individuals who are at greater risk of death due to cancer related and unrelated to HCV, as well as cardiovascular diseases, after viral eradication. Multicentre retrospective cohort studies including our study have suggested no increase in HCC recurrence and improved survival after DAA treatment.

Academic Significance and Societal Importance of the Research Achievements

研究分担者を中心に開発したヒトiPS細胞培養系を用いた肝疾患病態モデルを用いて行う点は独自性に富むものであり、未だ充分明らかとなっていないウイルス駆除後の肝発癌機構の解明、M2BPGiの機能的意義の解析に向けた慢性炎症モデルへの応用可能と考えられている。未だ充分明らかとなっていないウイルス駆除後の肝内および肝外病態におけるリスク因子としてM2BPGiが同定されたことは、効果的なSVR後サーベイランスを可能とし、個別化医療の発展などへの波及効果をもたらす可能性がある。

Research Products

• [Int'l Joint Research] Hospital Clinic de Barcelona(スペイン)
• [Int'l Joint Research] University of Palermo(イタリア)
• [Journal Article] Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis (2022)
  • Author(s): Tahata Y, Hikita H, Mochida S, Enomoto N, Kawada N, Kurosaki M, Ido A, Miki D, Yoshiji H, Takikawa Y, Sakamori R, Hiasa Y, Nakao K, Kato N, Ueno Y, Yatsuhashi H, Itoh Y, Tateishi R, Suda G, Takami T, Nakamoto Y, Asahina Y, et al.
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 2 Pages: 120-132
  • DOI: 10.1007/s00535-021-01845-5
  • Peer Reviewed
• [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] SVR後の発癌と生命予後 (2021)
  • Author(s): 中川美奈
  • Journal Title: 消化器・肝臓内科 Volume: 10 Pages: 724-731
• [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] Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study (2020)
  • Author(s): Tahata Yuki、Hikita Hayato、Matsuura Kentaro、Takehara Tetsuo, et al.
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 1 Pages: 67-77
  • DOI: 10.1007/s00535-020-01733-4
  • 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] .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] 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
• [Presentation] Factors associated with HCC development and patients’ survival in patients with an SVR. (2021)
  • Author(s): Mina Nakagawa, Masato Miyoshi, Fukiko Kawai-Kitahata, Miyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Yasuhiro Asahina
  • Organizer: JSH International Liver Conference
  • Int'l Joint Research
• [Presentation] C型慢性肝疾患SVR後の生命予後の検討 (2021)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] ヒトiPS細胞由来肝細胞系譜細胞を利用した肝細胞癌発生におけるMLL4の機能解析 (2021)
  • Author(s): 志水太郎、柿沼 晴、朝比奈靖浩
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 新規ヒトiPS細胞由来肝細胞オルガノイド系の構築と肝疾患研究 (2021)
  • Author(s): 三好正人、柿沼 晴、朝比奈靖浩
  • Organizer: 第25回日本肝臓学会大会
• [Presentation] C型肝硬変における抗ウイルス療法後の病態進展予測因子の検討 (2021)
  • Author(s): 村川美也子、中川美奈、朝比奈靖浩
  • Organizer: 第25回日本肝臓学会大会
• [Presentation] SVR後C型慢性肝疾患の生命予後の検討 (2021)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第107回日本消化器病学会総会
• [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、中川美奈、朝比奈靖浩、他
  • Organizer: 第20回 日本再生医療学会総会
  • Invited
• [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] C型慢性肝疾患SVR後肝発癌予測因子の検討 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] SVR後の肝発癌、生存予測因子の解析 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] C型慢性肝疾患SVR後の肝発癌および予後の検討 (2020)
  • Author(s): 中川美奈、村川美也子、朝比奈靖浩
  • Organizer: JDDW2020
• [Presentation] ヒトiPS細胞を用いた肝線維症における分子標的の探索 (2020)
  • Author(s): 柿沼 晴、角田知之、朝比奈靖浩
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] ヒトiPS細胞由来肝臓構成細胞の疾患モデルへの応用 (2020)
  • Author(s): 柿沼 晴
  • Organizer: 第27回肝細胞研究会
  • Invited
• [Presentation] C型慢性肝疾患DAA治療後の肝発癌および生命予後の検討 (2019)
  • Author(s): 中川 美奈、村川 美也子、朝比奈 靖浩
  • Organizer: JDDW2019
• [Presentation] C型肝炎の治療とPost SVR診療の問題点 (2019)
  • Author(s): 中川 美奈
  • Organizer: 2019年度日本肝臓学会教育講演会
  • Invited
• [Presentation] ウイルス制御下における肝発癌および長期予後―前向きコホートを用いたIFNベース治療とIFNフリー治療の比較検討― (2019)
  • Author(s): 中川 美奈、朝比奈 靖浩、村川 美也子
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] C型慢性肝疾患SVR後のde novo発癌，再発癌の検討 (2019)
  • Author(s): 中川 美奈、朝比奈 靖浩、渡辺 守
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] HCC occurrence/recurrence after HCV eradication (2019)
  • Author(s): Mina Nakagawa
  • Organizer: APASL single tipoc conference 2019
  • Int'l Joint Research / Invited
• [Presentation] Impact of HCV clearance on HCC development and patient survival: Propensity score-matched analysis of an ongoing database of 2173 CHC patients (2019)
  • Author(s): Nakagawa M, Asahina Y, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tomita M, Watanabe M
  • Organizer: The 54th annual meeting of the European association for the study of the liver
  • Int'l Joint Research
• [Presentation] 御茶ノ水リバーカンファレンスから発信する C型慢性肝炎の最新事情と諸問題 (2019)
  • Author(s): 中川 美奈
  • Organizer: 第19回御茶ノ水リバーカンファレンス
  • Invited
• [Book] 肝癌診療マニュアル第４版 (2020)
  • Author(s): 持田智、中川美奈 ほか日本肝臓学会、同企画広報委員
  • Total Pages: 278
  • Publisher: 医学書院
  • ISBN: 9784260040815
• [Book] 慢性肝炎・肝硬変の診療ガイド (2019)
  • Author(s): 持田智、中川美奈 ほか日本肝臓学会ガイド改訂委員
  • Total Pages: 85
  • Publisher: 文光堂
  • ISBN: 9784830621055
• [Remarks] 東京医科歯科大学 消化器内科 研究（肝臓）
  • URL: https://www.tmd.ac.jp/grad/gast/research/liver.html
• [Remarks] 東京医科歯科大学 消化器内科 専門外来で行われている臨床研究について
  • URL: https://www.tmd.ac.jp/grad/gast/medical/ld_rinsyo.html