Basic research to develop next generation cell therapy for improvement of liver fibrosis.

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26293175
• Research Institution: Niigata University
• Principal Investigator: 寺井 崇二 新潟大学, 医歯学系, 教授 (00332809)
• Co-Investigator(Kenkyū-buntansha): 佐藤 祐一 新潟大学, 医歯学総合病院, 准教授 (00401761) ; 上村 顕也 新潟大学, 医歯学系, 助教 (00579146) ; 山際 訓 新潟大学, 医歯学系, 准教授 (10419327) ; 土屋 淳紀 新潟大学, 医歯学総合病院, 助教 (70464005) ; 川合 弘一 新潟大学, 医歯学総合病院, 講師 (80419291)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 肝硬変 / 細胞療法 / 間葉系幹細胞 / マクロファージ

Outline of Annual Research Achievements

非代償性肝硬変では原因除去後も線維化改善せず進行性である症例を経験し、こうした症例に線維化改善と再生促進を目指す肝再生医療への展開が望まれている。自己骨髄投与療法（ABMi療法）は本邦で最も行われている細胞療法であるが、骨髄細胞はヘテロであり有効な細胞とそのメカニズム、投与後の動態など未解明の部分がある。今回我々はヘテロの細胞中の骨髄細胞中の間葉系幹細胞(MSC)とマクロファージ(BMM)を用いてin vitroおよびin vivoでの線維化改善、再生促進のメカニズムに迫った。我々はin vitroでの発現解析から両細胞を同時投与すると効率よく線維化改善が起こる可能性を考えその証明のために両細胞を50:50で混合投与(50/50)を行い(各1×106個/匹)、仮説通り両細胞の投与で効率よく四塩化炭素(CCl4)誘導肝硬変モデルにおいて効率よく肝線維化改善再生促進が行われることを発見した。また、投与した細胞動態観察にGFP陽性のBMMとDsRed陽性のMSCを用いて二光子励起顕微鏡によるLive Imagingを行いMSCは主に肺にトラップされ、マクロファージが主に肝臓に行くことを初めて突き止めた。投与後の線維化改善、再生促進のメカニズムでとして、M2に極性変化したマクロファージが重要な細胞であることも突き止めた。投与マクロファージはM2方向に極性変化し、線維溶解に関わるMMP群を強く発現するようになり、また貪食能力も強くなり、壊死肝細胞を貪食し肝再生因子のoncostatin Mなども産生することを明らかにした。更に投与細胞ばかりでなくホスト側の好中球・単球も細胞投与後肝内に動員され線維化改善・再生促進因子に深く関わることを突き止めた。本研究により、肝硬変の細胞療法のメカニズムの不明瞭な部分が解明に向け大きく前進し、今後細胞療法を展開する上で重要な指針を与えるものと考える。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Causes of Carryover

28年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Status of and candidates for cell therapy in liver cirrhosis: overcoming the "point of no return" in advanced liver cirrhosis. (2017)
  • Author(s): Terai S, Tsuchiya A.
  • Journal Title: J Gastroenterol. Volume: Feb;52(2) Pages: 129-140.
  • DOI: 10.1007/s00535-016-1258-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions. (2017)
  • Author(s): Suzuki K, Yokoyama J, Kawauchi Y, Honda Y, Sato H, Aoyagi Y, Terai S, Okazaki K, Suzuki Y, Sameshima Y, Fukushima T, Sugahara K, Atreya R, Neurath MF, Watanabe K, Yoneyama H, Asakura H:
  • Journal Title: Journal of Crohn's & colitis Volume: Feb;11(2) Pages: 221-228.
  • DOI: 10.1093/ecco-jcc/jjw143.
  • Peer Reviewed
• [Journal Article] Long-term outcomes of colorectal endoscopic submucosal dissection in elderly patients. International journal of colorectal disease (2017)
  • Author(s): Takahashi Y, Mizuno KI, Takahashi K, Sato H, Hashimoto S, Takeuchi M, Kobayashi M, Yokoyama J, Sato Y, Terai S
  • Journal Title: International journal of colorectal disease Volume: Apr;32(4): Pages: 567-573
  • DOI: 10.1007/s00384-016-2719-y
  • Peer Reviewed
• [Journal Article] Muscle layer histopathology and manometry pattern of primary esophageal motility disorders including achalasia. (2017)
  • Author(s): Nakajima N, Sato H, Takahashi K, Hasegawa G, Mizuno K, Hashimoto S, Sato Y, Terai S.
  • Journal Title: Neurogastroenterol Motil. Volume: Mar;29(3). Pages: in press
  • DOI: 10.1111/nmo.12968
  • Peer Reviewed
• [Journal Article] Natural regression of fibrosis in chronic hepatitis B. (2016)
  • Author(s): Ohkoshi S, Hirono H, Watanabe K, Hasegawa K, Kamimura K, Yano M.
  • Journal Title: World J Gastroenterol Volume: 22 Pages: 5459-5466
  • DOI: 10.3748/wjg.v22.i24.5459
  • Peer Reviewed
• [Journal Article] Identification of BCL11B as a regulator of adipogenesis. (2016)
  • Author(s): Inoue J, Ihara Y, Tsukamoto D, Yasumoto K, Hashidume T, Kamimura K, Nakai Y, Hirano S, Shimizu M, Kominami R, Sato R.
  • Journal Title: Sci Rep Volume: 6: 32750. Pages: 1-13
  • DOI: doi: 10.1038/srep.
  • Peer Reviewed / Open Access
• [Journal Article] Effects of fibrotic tissue on liver-targeted hydrodynamic gene delivery. (2016)
  • Author(s): Kobayashi Y, Kamimura K, Abe H, Yokoo T, Ogawa K, Shinagawa Y, Goto R, Inoue R, Ohtsuka M, Miura H, Kanefuji T, Suda T, Tsuchida M, Aoyagi Y, Zhang G, Liu D, Terai S.
  • Journal Title: Mol Ther Nucleic Acids Volume: . 5: e359. Pages: 1-8
  • DOI: 10.1038/mtna.2016.63.
  • Peer Reviewed / Open Access
• [Journal Article] The Liver-targeted Hydrodynamic Gene Therapy: Recent Advances in the Technique. (2016)
  • Author(s): Yokoo T, Kamimura K, Abe H, Kobayashi Y, Kanefuji T, Ogawa K, Goto R, Suda T, Oda M, and Terai S.
  • Journal Title: World J Gastroenterol Volume: 22: Pages: 8862-8868
  • DOI: 10.3748/wjg.v22.i40.8862
  • Peer Reviewed
• [Journal Article] Case of severe alcoholic hepatitis treated with granulocytapheresis. (2016)
  • Author(s): Watanabe Y, Kamimura K, Iwasaki T, Abe H, Takahashi S, Mizuno KI, Takeuchi M, Eino A, Narita I, Terai S.
  • Journal Title: World J Clin Cases Volume: 4: Pages: 369-374.
  • DOI: 12998/wjcc.v4.i11.369
  • Peer Reviewed / Open Access
• [Journal Article] The combination therapy of dissolution using carbonated liquid and endoscopic procedure for bezoars: pragmatical and clinical review (2016)
  • Author(s): Ogawa K, Kamimura K, Mizuno KI, Shinagawa Y, Kobayashi Y, Abe H, Watanabe Y, Takahashi S, Hayashi K, Yokoyama J, Takeuchi M, Kobayashi M, Yamagiwa S, Sato Y, Terai S.
  • Journal Title: Gastroenterol Res Pract Volume: 7456242 Pages: 1-11
  • DOI: 10.1155/2016/7456242
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and management of gastrointestinal foreign bodies. (2016)
  • Author(s): Kamimura K, Evans DC, Mizuno KI, Sola JE.
  • Journal Title: Gastroenterol Res Pract Volume: 5692650 Pages: 1-2
  • DOI: 10.1155/2016/5692650
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endoscopic Removal of Ingested Dentures and Dental Instruments: A Retrospective Analysis. (2016)
  • Author(s): Mizuno KI, Takahashi K, Tominaga K, Nishigaki Y, Sato H, Ikarashi S, Hayashi K, Yamamoto T, Honda Y, Hashimoto S, Kamimura K, Takeuchi M, Yokoyama J, Sato Y, Kobayashi M, Terai S:
  • Journal Title: Gastroenterology research and practice. Volume: 3537147 Pages: 1-5
  • DOI: 10.1155/2016/3537147
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis (2016)
  • Author(s): Suzuki K, Arumugam S, Yokoyama J, Kawauchi Y, Honda Y, Sato H, Aoyagi Y, Terai S, Okazaki K, Suzuki Y, Mizumoto S, Sugahara K, Atreya R, Neurath MF, Watanabe K, Hashiguchi T, Yoneyama H, Asakura H: .
  • Journal Title: PloS one Volume: 11 Pages: 1-17
  • DOI: 10.1371/journal.pone.0158967
  • Peer Reviewed / Open Access
• [Journal Article] A novel training model composed of nonbiological materials for endoscopic submucosal dissection. (2016)
  • Author(s): Mizuno K, Sato H, Hashimoto S, Sato Y, Terai S
  • Journal Title: Gastrointestinal endoscopy Volume: 84 Pages: 373-374
  • DOI: 10.1016/j.gie.2016.03.786
  • Peer Reviewed
• [Journal Article] An Unusual Case of an Extremely Large α-Fetoprotein-Producing Tumor. (2016)
  • Author(s): Takahashi K, Tsuchiya A, Terai S.
  • Journal Title: Gastroenterology. Volume: Dec;151(6): Pages: 1077-1080.
  • DOI: 10.1053/j.gastro.2016.08.018. 
  • Peer Reviewed
• [Journal Article] Stomach Dysfunction Is a Potential Risk Factor for Wernicke's Encephalopathy. (2016)
  • Author(s): Nakano O, Tsuchiya A, Yamagiwa S, Terai S.
  • Journal Title: Intern Med. Volume: 55(24) Pages: :3679-3680
  • DOI: 10.2169/internalmedicine.55.7483
  • Peer Reviewed
• [Journal Article] Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: Interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study). (2016)
  • Author(s): Sakaida I, Terai S, Kurosaki M, Yasuda M, Okada M, Bando K, Fukuta Y.
  • Journal Title: Hepatol Res. Volume: Dec 13. Pages: in press
  • DOI: 10.1111/hepr.12852
  • Peer Reviewed
• [Journal Article] Vonoprazan 20 mg vs lansoprazole 30 mg for endoscopic submucosal dissection-induced gastric ulcers. (2016)
  • Author(s): Takahashi K, Sato Y, Kohisa J, Watanabe J, Sato H, Mizuno K, Hashimoto S, Terai S.
  • Journal Title: World J Gastrointest Endosc. Volume: Nov 16;8(19): Pages: 716-722.
  • DOI: 10.4253/wjge.v8.i19.716
  • Peer Reviewed
• [Journal Article] Myofibroblast distribution is associated with invasive growth types of colorectal cancer (2016)
  • Author(s): Takatsuna M, Morohashi S, Yoshizawa T, Hirai H, Haga T, Ota R, Saito K, Wu Y, Seino H, Aoyagi Y, Terai S, Kijima H.
  • Journal Title: Oncol Rep. Volume: Dec;36(6): Pages: .3154-3160.
  • DOI: 10.3892/or.2016.5202.
  • Peer Reviewed
• [Journal Article] Risk of metastasis in adenocarcinoma of the esophagus: a multicenter retrospective study in a Japanese population. (2016)
  • Author(s): Ishihara R, Oyama T, Terai S, Ozawa S, Kawano T, Seto Y et al.
  • Journal Title: J Gastroenterol. Volume: Oct 18. Pages: in press
  • DOI: 10.1007/s00535-016-1275-0
  • Peer Reviewed
• [Journal Article] Management of gastric and duodenal neuroendocrine tumors. (2016)
  • Author(s): Sato Y, Hashimoto S, Mizuno K, Takeuchi M, Terai S.
  • Journal Title: World J Gastroenterol. Volume: Aug 14;22(30): Pages: 6817-28
  • DOI: 10.3748/wjg.v22.i30.6817.
  • Peer Reviewed
• [Journal Article] Therapeutic or spontaneous Helicobacter pylori eradication can obscure magnifying narrow-band imaging of gastric tumors. (2016)
  • Author(s): Kobayashi M, Hashimoto S, Mizuno K, Takeuchi M, Sato Y, Watanabe G, Ajioka Y, Azumi M, Akazawa K, Terai S.
  • Journal Title: Endosc Int Open. Volume: Jun;4(6): Pages: E665-72.
  • DOI: 10.1055/s-0042-105869
  • Peer Reviewed / Open Access
• [Journal Article] Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer. (2016)
  • Author(s): Takatsuna M, Morohashi S, Yoshizawa T, Hirai H, Haga T, Ota R, Wu Y, Morohashi H, Hakamada K, Terai S, Kijima H.
  • Journal Title: Oncol Rep Volume: Sep;36(3): Pages: 1251-7
  • DOI: 10.3892/or.2016.4932. 
  • Peer Reviewed
• [Journal Article] Formulation for Effective Screening and Management of Nonalcoholic Steatohepatitis: Noninvasive NAFLD Management Strategy. (2016)
  • Author(s): Hirose K, Kanefuji T, Suda T, Sugitani S, Nagasaki K, Kubota T, Igarashi M, Terai S.
  • Journal Title: Gastroenterol Res Pract. Volume: 6343656 Pages: 1-9
  • DOI: 10.1155/2016/6343656.
  • Peer Reviewed / Open Access
• [Journal Article] Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib. (2016)
  • Author(s): Yamamoto N, Yamasaki T, Takami T, Uchida K, Fujisawa K, Matsumoto T, Saeki I, Terai S, Sakaida I.
  • Journal Title: J Clin Biochem Nutr. Volume: May;58(3): Pages: 202-9.
  • DOI: 0.3164/jcbn.15-127
  • Peer Reviewed
• [Journal Article] Novel ex-vivo training model for peroral endoscopic myotomy using hydrogel. (2016)
  • Author(s): Sato H, Mizuno K, Terai S.
  • Journal Title: Dig Endosc. Volume: Jul;28(5): Pages: 620.
  • DOI: 10.1111/den.12670
  • Peer Reviewed
• [Journal Article] Gastrointestinal: Salvage peroral endoscopic myotomy for outflow obstruction with growing esophageal diverticulum. (2016)
  • Author(s): Sato H, Sato Y, Hashimoto S, Mizuno K, Nakajima N, Terai S.
  • Journal Title: J Gastroenterol Hepatol. Volume: Jul;31(7): Pages: 1237.
  • DOI: 10.1111/jgh.13397
  • Peer Reviewed
• [Journal Article] Three Times Repeated Portal Venous Gas after Meals. (2016)
  • Author(s): Kobayashi T, Tsuchiya A, Suda T, Terai S.
  • Journal Title: Intern Med. Volume: 55(7): Pages: 843-5.
  • DOI:  10.2169/internalmedicine.55.6036.
  • Peer Reviewed
• [Journal Article] Assessments of histologic changes after peroral endoscopic myotomy. (2016)
  • Author(s): Sato H, Sagara S, Suzuki K, Terai S, Yahagi N.
  • Journal Title: Gastrointest Endosc. Volume: Aug;84(2): Pages: 377-8.
  • DOI: 10.1016/j.gie.2016.01.011.
  • Peer Reviewed
• [Journal Article] Improvement of Pancreatic Tumor-induced NAFLD with Pancrelipase. (2016)
  • Author(s): Kuraoka N, Tsuchiya A, Suda T, Terai S.
  • Journal Title: Intern Med. Volume: 55(1): Pages: 89-90.
  • DOI: 10.2169/internalmedicine.55.5729
  • Peer Reviewed
• [Journal Article] A Rare Pancreatic Tumor That Underwent a Change in Morphology and Histopathologic Features During Chemotherapy. (2016)
  • Author(s): Seino S, Tsuchiya A, Natsui M.
  • Journal Title: Gastroenterology Volume: Feb;150(2) Pages: e11-3
  • DOI: 10.1053/j.gastro.2015.06.049
  • Peer Reviewed
• [Presentation] 肝硬変に対する自己由来細胞を用いた再生療法から他家細胞を用いた再生医療へ (2017)
  • Author(s): 寺井崇二、土屋淳紀
  • Organizer: 日本再生医療学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-07 – 2017-03-09
• [Presentation] 骨髄由来間葉系幹細胞と培養マクロファージの混合投与療法による肝硬変治療 (2017)
  • Author(s): 渡邉雄介、土屋淳紀、寺井崇二
  • Organizer: 日本再生医療学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-07 – 2017-03-09
• [Presentation] 間葉系幹細胞、マクロファージの相互作用による新しい肝硬変治療を目指して (2016)
  • Author(s): 土屋淳紀
  • Organizer: 日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-12-08 – 2016-12-09
• [Presentation] Frequency of CCR7-PD-1+ follicular helper T cell subset as a possible diagnostic marker of autoimmune hepatitis (2016)
  • Author(s): 山際訓
  • Organizer: AASLD 2016
  • Place of Presentation: Boston (USA)
  • Year and Date: 2016-11-11 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Significance of hepatic progenitor cell marker-positive hepatocellular carcinoma and its possible prediction by AFP-L3 (2016)
  • Author(s): 土屋淳紀
  • Organizer: AASLD 2016
  • Place of Presentation: Boston (USA)
  • Year and Date: 2016-11-11 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Combination therapy with mesenchymal stem cells and macrophages from bone marrow shows favorable outcome in mouse CCl4-induced liver cirrhosis model (2016)
  • Author(s): 渡邉雄介、土屋淳紀、寺井崇二
  • Organizer: AASLD 2016
  • Place of Presentation: Boston (USA)
  • Year and Date: 2016-11-11 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Platinum-based transhepatic arterial chemotherapy using a combination miriplatin and CDDP powder in patients with hepatocellular carcinoma (2016)
  • Author(s): 小川光平、上村顕也、寺井崇二
  • Organizer: AASLD 2016
  • Place of Presentation: Boston (USA)
  • Year and Date: 2016-11-11 – 2016-11-15
  • Int'l Joint Research
• [Presentation] Transhepatic arterial chemotherapy using a combination of miriplatin and CDDP powder in patients with hepatocellular carcinoma. (2016)
  • Author(s): 上村顕也
  • Organizer: APDW 2016
  • Place of Presentation: Kobe Convention Center (兵庫県神戸市）
  • Year and Date: 2016-11-02 – 2016-11-05
  • Int'l Joint Research
• [Presentation] Comparative effectiveness of mesenchymal stem cell therapy and macrophage cell therapy in a liver cirrhosis disease model (2016)
  • Author(s): 土屋淳紀
  • Organizer: APDW 2016
  • Place of Presentation: Kobe Convention Center (兵庫県神戸市）
  • Year and Date: 2016-11-02 – 2016-11-05
  • Int'l Joint Research
• [Presentation] Histological and Transcriptomic Analysis of Japanese Medaka Fish Sampled Onboard the International Space Station (2016)
  • Author(s): 寺井崇二
  • Organizer: APDW 2016
  • Place of Presentation: Kobe Convention Center (兵庫県神戸市）
  • Year and Date: 2016-11-02 – 2016-11-05
  • Int'l Joint Research
• [Presentation] Effective Prevention of Liver Fibrosis by Hydrodynamic Gene Delivery (2016)
  • Author(s): 阿部寛幸
  • Organizer: FASEB 2016
  • Place of Presentation: Florida (USA)
  • Year and Date: 2016-06-26 – 2016-07-01
  • Int'l Joint Research
• [Presentation] Histological and Transcriptomic Analysis of Japanese Medaka Fish Sampled Onboard the International Space Station (2016)
  • Author(s): 寺井崇二
  • Organizer: FASEB 2016
  • Place of Presentation: Florida (USA)
  • Year and Date: 2016-06-26 – 2016-07-01
  • Int'l Joint Research
• [Presentation] 難治性消化器疾患に対する修復再生療法の開発 (2016)
  • Author(s): 寺井崇二
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: みやこめっせ（京都府京都市）
  • Year and Date: 2016-06-16 – 2016-06-17
  • Invited
• [Presentation] 肝硬変の治療メカニズム解析のための骨髄由来のMSC,マクロファージ培養および解析 (2016)
  • Author(s): 土屋淳紀
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: みやこめっせ（京都府京都市）
  • Year and Date: 2016-06-16 – 2016-06-17