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

• Project/Area Number: 16H05282
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: Sakamoto Naoya 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 肝線維化 / 消化器内科 / 内科 / 肝硬変 / 肝線維症 / 間葉系幹細胞 / 間葉系 幹細胞

Outline of Final Research Achievements

The present study was conducted to search for therapeutic candidates (peptides, small molecules and miRNAs) to target liver fibrosis and activation of hepatic stellate cells and to analyze their mechanisms of action. The main results are as follows; (1) We confirmed suppressive effects of liver fibrosis and inflammation of exosomes derived from the culture supernatant of human amniotic membrane-derived mesenchymal stem cells. (2) palmitoylethanolamide (PEA) inhibited activation of hepatic stellate cells through PPAR-independent mechanisms. (3) Comprehensive glycan modification structure analysis indentified fucosyl modification of serum proteins as markers that associate with NAFL to NASH progression. (4) Comprehensive analysis of microRNAs related to cultured hepatic stellate cell activation identified miRNAs that up- or down-regulated in activated stellate cells.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、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開発の基盤となる。肝疾患と糖鎖発現変動に関する研究は多数報告があるが、主要な全てのクラスの糖鎖の包括的な解析例はない。包括的糖鎖修飾解析の結果同定された特異修飾糖鎖は、非侵襲的診断マーカーとしてのみならず、糖鎖構造に対する抗体、結合小分子を大規模探索し、糖鎖修飾構造を標的とした分子標的治療が構築される可能性がある。

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 Issue: 1 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 Kana、Ono Shoko、Ishikawa Marin、Miyamoto Shuichi、Abiko Satoshi、Tsuda Momoko、Yamamoto Keiko、Kudo Takahiko、Shimizu Yuichi、Hayase Eiko、Hashimoto Daigo、Teshima Takanori、Matsuno Yoshihiro、Sakamoto Naoya
  • Journal Title: Annals of Hematology Volume: 97 Issue: 5 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 Issue: 2 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: 723-723
  • 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 Issue: 1 Pages: e000206-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: 709-709
  • DOI: 10.3389/fphar.2018.00709
  • NAID: 120006522665
  • Peer Reviewed / Open Access
• [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
  • NAID: 120006528265
  • 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: 90 Issue: 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: 4898152-4898152
  • DOI: 10.1155/2018/4898152
  • NAID: 120006541895
  • 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 Naoki、Suda Goki、Nakamura Akinobu、Kimura Megumi、Maehara Osamu、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Izumi Takaaki、Umemura Machiko、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Miyoshi Hideaki、Sakamoto Naoya
  • Journal Title: PLOS ONE Volume: 13 Issue: 12 Pages: 615-620
  • DOI: 10.1371/journal.pone.0209615
  • NAID: 120006866533
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats (2018)
  • Author(s): Ohara Masatsugu、Ohnishi Shunsuke、Hosono Hidetaka、Yamamoto Koji、Yuyama Kohei、Nakamura Hideki、Fu Qingjie、Maehara Osamu、Suda Goki、Sakamoto Naoya
  • Journal Title: Stem Cells International Volume: 2018 Pages: 1-15
  • DOI: 10.1155/2018/3212643
  • NAID: 120006585982
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction (2018)
  • Author(s): Sho T, Suda G,, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Uebayashi M, Terashita K, Kobayashi T, Tsunematsu I, Onodera M, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Kawagishi N, Ohara M, Ono Y, Nakai M, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N
  • Journal Title: Heptology Research Volume: in press Issue: 7 Pages: 529-538
  • DOI: 10.1111/hepr.13056
  • Peer Reviewed
• [Journal Article] Treatment of hepatitis C in special populations. (2018)
  • Author(s): Suda G, Ogawa K, Morikawa K, Sakamoto N
  • Journal Title: Journal of Gastroenterology Volume: in press Issue: 5 Pages: 591-605
  • DOI: 10.1007/s00535-017-1427-x
  • Peer Reviewed / Open Access
• [Journal Article] Increased serum C-reactive protein and decreased urinary aquaporin 2 levels are predictive of the efficacy of tolvaptan in patients with liver cirrhosis (2018)
  • Author(s): 3.Nakai M, Ogawa K, Takeda R, Ohara M, Kawagishi N, Izumi T, Umemura M, Ito J, Sho T, Suda G, Morikawa K, Sakamoto N
  • Journal Title: Hepatolgy Research Volume: in press Issue: 3
  • DOI: 10.1111/hepr.12988
  • NAID: 120006551584
  • Peer Reviewed
• [Journal Article] Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors. (2017)
  • Author(s): Hontani K, Tsuchikawa T, Hiwasa T, Nakamura T, Ueno T, Kushibiki T, Takahashi M, Inoko K, Takano H, Takeuchi S, Dosaka-Akita H, Kuwatani M, Sakamoto N, Hatanaka Y, Mitsuhashi T, Shimada H, Shichinohe T, Hirano S.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106206-106221
  • DOI: 10.18632/oncotarget.22175
  • NAID: 120006416017
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma (2017)
  • Author(s): Osamu Maehara, Goki Suda et al.
  • Journal Title: Carcinogenesis Volume: 38 Issue: 11 Pages: 1073-1083
  • DOI: 10.1093/carcin/bgx095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C virus-induced innate immune responses in human iPS cell-derived hepatocyte-like cells (2017)
  • Author(s): Sakurai Fuminori、Kunito Takemaru、Takayama Kazuo、Hashimoto Rina、Tachibana Masashi、Sakamoto Naoya、Wakita Takaji、Mizuguchi Hiroyuki
  • Journal Title: Virus Research Volume: 242 Pages: 7-15
  • DOI: 10.1016/j.virusres.2017.09.004
  • Peer Reviewed
• [Journal Article] Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit. (2017)
  • Author(s): Arima, Y., T. Ohki, N. Nishikawa, K. Higuchi, M. Ota, Y. Tanaka, J. Nio-Kobayashi, M. Elfeky, R. Sakai, Y. Mori, T. Kawamoto, A. Stofkova, Y. Sakashita, Y. Morimoto, M. Kuwatani, T. Iwanaga, Y. Yoshioka, N. Sakamoto, A. Yoshimura, M. Takiguchi, S. Sakoda, M. Prinz, D. Kamimura, M. Murakami.
  • Journal Title: eLife Volume: 6:e25517 Pages: 1-27
  • DOI: 10.7554/elife.25517
  • NAID: 120006360081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C (2017)
  • Author(s): Kawagishi N.、Suda G.、Onozawa M.、Kimura M.、Maehara O.、Ohara M.、Izumi T.、Umemura M.、Ito J.、Nakai M.、Sho T.、Natsuizaka M.、Morikawa K.、Ogawa K.、Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: 24 Issue: 12 Pages: 1098-1106
  • DOI: 10.1111/jvh.12737
  • Peer Reviewed
• [Journal Article] Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan (2017)
  • Author(s): Suda Goki、Morikawa Kenichi、et al.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 1 Pages: 119-128
  • DOI: 10.1007/s00535-017-1353-y
  • Peer Reviewed
• [Journal Article] Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Honda M, et al.
  • Journal Title: Gastroenterology. Volume: - Issue: 6 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Paradoxical Effects of Different Hepatitis C Viral Loads on Host DNA Damage and Repair Abilities. (2017)
  • Author(s): Wang SC, Lai KR, Li CY, Chiang CS, Yu GY, Sakamoto N, Tu WY, Hsieh MH, Huang JF, Chuang WL, Dai CY, Yu ML
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: 1-1
  • DOI: 10.1371/journal.pone.0164281
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatitis B virus X protein impairs α-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A. (2017)
  • Author(s): Tsunematsu S, Suda G, Yamasaki K, Kimura M, Izumi T, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Tanaka Y, Watashi K, Wakita T, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 2 Pages: 267-275
  • DOI: 10.1002/jmv.24643
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Retinoid derivative Tp80 exhibits anti-hepatitis C virus activity through restoration of GI-GPx expression. (2017)
  • Author(s): Ngoc NB, Okuno Y, Ajiro M, Iida K, Denawa M, Yamamoto M, Sakamoto N, Kagechika H, Hagiwara M
  • Journal Title: J Med Virol Volume: Epub ahead of print Issue: 7 Pages: 1224-1234
  • DOI: 10.1002/jmv.24739
  • Peer Reviewed
• [Journal Article] Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection. (2016)
  • Author(s): Tsukuda Y, Suda G, Tsunematsu S, Ito J, Sato F, Terashita K, Nakai M, Sho T, Maehara O, Shimazaki T, Kimura M, Morikawa K, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 5 Pages: 857-866
  • DOI: 10.1002/jmv.24692
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 羊膜由来間葉系幹細胞の消化器疾患への治療応用 (2018)
  • Author(s): 大西俊介，山本幸司，坂本直哉
  • Organizer: 第17回日本再生医療学会総会