Search for new cell- or small molecule-based therapies to promote regression of liver cirrohsis

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H05282
• Research Institution: Hokkaido University
• Principal Investigator: 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): 大西 俊介 北海道大学, 医学研究院, 准教授 (10443475) ; 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460) ; 森川 賢一 北海道大学, 医学研究院, 助教 (60384377)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 消化器内科 / 肝線維化

Outline of Annual Research Achievements

本研究は，従来非可逆的とされていた肝硬変症の組織病態を積極的に修復する手法を開発するために，肝硬変の組織病態の修復機構を解析し、肝星細胞を標的とした細胞・薬物療法による肝線維化の組織修復を促進する治療法の効果、作用機構等を解析することを目的として遂行し、以下の成果を得た。
1. 昨年度に確立した羊膜MSC由来エクソソームの分離・精製法をもとに，四塩化炭素誘発肝線維症モデルに対して羊膜MSC由来エクソソームの静脈内投与を行い，線維化抑制，kupffer細胞の浸潤ならびに炎症性サイトカインの発現抑制が確認され，in vitroの系でも羊膜MSC由来エクソソームの炎症反応抑制効果が確認された．また，羊膜MSCから分泌される低分子生理活性物質として，脂肪酸アミドであるpalmitoylethanolamide (PEA)に着目し，PEAのPPAR非依存的な炎症抑制効果ならびに星細胞活性化抑制作用をin vitroの系で明らかにし，非アルコール性脂肪性肝炎モデルおよび四塩化炭素誘発肝線維症モデルに対するPEAの炎症抑制効果・線維化抑制効果を確認した．
2. 培養肝星細胞活性化に関連するmicro RNAの包括的解析を施行し、特定のmiRNAが活性化星細胞で高発現し、knock downにより星細胞alpha-SMA、type-I collagen発現が抑制されることを示した。
以上のことから，羊膜MSCから分泌される液性因子として，エクソソームおよびPEAの抗炎症効果，星細胞活性化抑制効果が明らかとなった．細胞治療におけるパラクライン効果に寄与するものと考えられた．

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Mesenchymal stem cell therapy for acute and chronic pancreatitis. (2018)
  • Author(s): Kawakubo K, Ohnishi S, Kuwatani M, Sakamoto N
  • Journal Title: J Gastroenterol Volume: 53 Pages: 1-5
  • DOI: 10.1007/s00535-017-1363-9
  • Peer Reviewed
• [Journal Article] Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. (2018)
  • Author(s): Matsuda K, Ono S, Ishikawa M, Miyamoto S, Abiko S, Tsuda M, Yamamoto K, Kudo T, Shimizu Y, Hayase E, Hashimoto D, Teshima T, Matsuno Y, Sakamoto N
  • Journal Title: Ann Hematol Volume: 97 Pages: 877-883
  • DOI: 10.1007/s00277-018-3241-9
  • Peer Reviewed
• [Journal Article] Conditioned Medium Obtained from Amnion-Derived Mesenchymal Stem Cell Culture Prevents Activation of Keloid Fibroblasts. (2018)
  • Author(s): Sato C, Yamamoto Y, Funayama E, Furukawa H, Oyama A, Murao N, Hosono H, Kawakubo K, Sakamoto N, Ohnishi S
  • Journal Title: Plast Reconstr Surg Volume: 141 Pages: 390-398
  • DOI: 10.1097/PRS.0000000000004068
  • Peer Reviewed
• [Journal Article] Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids. (2018)
  • Author(s): Cai C, Koch B, Morikawa K, Suda G, Sakamoto N, Rueschenbaum S, Akhras S, Dietz J, Hildt E, Zeuzem S, Welsch C, Lange CM
  • Journal Title: Front Immunol Volume: 9 Pages: 723
  • DOI: 10.3389/fimmu.2018.00723
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of interferon signaling and HCV-RNA replication by extracellular matrix. (2018)
  • Author(s): Kuwashiro T, Iwane S, Jinghe X, Matsuhashi S, Eguchi Y, Anzai K, Fujimoto K, Mizuta T, Sakamoto N, Ikeda M, Kato N, Ozaki I
  • Journal Title: Int J Mol Med Volume: 42 Pages: 957-965
  • DOI: 10.3892/ijmm.2018.3693
  • Peer Reviewed
• [Journal Article] Evaluation of amnion-derived mesenchymal stem cells for treatment-resistant moderate Crohn's disease: study protocol for a phase I/II, dual-centre, open-label, uncontrolled, dose-response trial. (2018)
  • Author(s): Otagiri S, Ohnishi S, Miura A, Hayashi H, Kumagai I, Ito YM, Katsurada T, Nakamura S, Okamoto R, Yamahara K, Cho KY, Isoe T, Sato N, Sakamoto N
  • Journal Title: BMJ Open Gastroenterol Volume: 5 Pages: e000206
  • DOI: 10.1136/bmjgast-2018-000206
  • Peer Reviewed
• [Journal Article] Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats. (2018)
  • Author(s): Ohara M, Ohnishi S, Hosono H, Yamamoto K, Fu Q, Maehara O, Suda G, Sakamoto N
  • Journal Title: Front Pharmacol Volume: 9 Pages: 709
  • DOI: 10.3389/fphar.2018.00709
  • Peer Reviewed
• [Journal Article] Effects of human amnion-derived mesenchymal stem cells and conditioned medium in rats with sclerosing cholangitis. (2018)
  • Author(s): Sugiura R, Ohnishi S, Ohara M, Ishikawa M, Miyamoto S, Onishi R, Yamamoto K, Kawakubo K, Kuwatani M, Sakamoto N
  • Journal Title: Am J Transl Res Volume: 10 Pages: 2102-2114
  • Peer Reviewed
• [Journal Article] Sialic Acid Linkage Specific Derivatization of Glycosphingolipid Glycans by Ring-Opening Aminolysis of Lactones. (2018)
  • Author(s): Hanamatsu H, Nishikaze T, Miura N, Piao J, Okada K, Sekiya S, Iwamoto S, Sakamoto N, Tanaka K, Furukawa JI
  • Journal Title: Anal Chem Volume: 22 Pages: 13193-13199
  • DOI: 10.1021/acs.analchem.8b02775
  • Peer Reviewed
• [Journal Article] Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells. (2018)
  • Author(s): Fu Q, Ohnishi S, Sakamoto N
  • Journal Title: Stem Cells Int Volume: 20 Pages: 4898152
  • DOI: 10.1155/2018/4898152
  • Peer Reviewed
• [Journal Article] Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis. (2018)
  • Author(s): Kawagishi N, Suda G, Nakamura A, Kimura M, Maehara O, Suzuki K, Nakamura A, Ohara M, Izumi T, Umemura M, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Kudo Y, Nishida M, Miyoshi H, Sakamoto N
  • Journal Title: PLoS One Volume: 13 Pages: e0209615
  • DOI: 10.1371/journal.pone.0209615
  • Peer Reviewed
• [Journal Article] Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats. (2018)
  • Author(s): Ohara M, Ohnishi S, Hosono H, Yamamoto K, Yuyama K, Nakamura H, Fu Q, Maehara O, Suda G, Sakamoto N
  • Journal Title: Stem Cells Int Volume: 201 Pages: 3212643
  • DOI: 10.1155/2018/3212643
  • Peer Reviewed