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Development of cell-free liver regeneration therapy with the anticipatory method to culture higher-quality MSCs for liver cirrhosis

Research Project

Project/Area Number 17K09428
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionYamaguchi University

Principal Investigator

TAKAMI Taro  山口大学, 医学部, 講師 (60511251)

Co-Investigator(Kenkyū-buntansha) 藤澤 浩一  山口大学, 医学部, 助教 (00448284)
松本 俊彦  山口大学, 大学院医学系研究科, 助教 (70634723)
山本 直樹  山口大学, 大学教育機構, 准教授 (90448283)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords肝硬変症 / 再生療法 / 間葉系幹細胞 / 細胞外小胞 / エクソソーム / 骨髄細胞 / 肝再生 / 肝硬変 / 肝臓再生
Outline of Final Research Achievements

Bone marrow derived mesenchymal stem cells (BM-MSCs) are a promising source of cells for regenerative medicine and clinical trials have been widely performed to explore their potential. In this study, we created a conditioned medium with whole BM cells (BM cells-conditioned medium; BMC-CM) to reproduce the BM microenvironment. As a result, BMC-CM suppressed morphological deterioration, proliferative decline, and mitochondrial oxidative phosphorylation activity in cultured BM-MSCs. Furthermore, BMC-CM upregulated TNF-stimulated gene 6 in BM-MSCs and the infusion of cultured BM-MSCs with BMC-CM improved liver fibrosis in rat carbon tetrachloride-induced liver cirrhosis. Thus, our developed method to culture higher-quality BM-MSCs using whole BM-derived factors might contribute to develop the higher therapeutic effects of liver regenerative therapy on liver cirrhosis.

Academic Significance and Societal Importance of the Research Achievements

治療効果と安全性を高めた肝臓再生療法を開発するには「高機能・高品質な骨髄MSC」の新規培養法の開発が必要であったが、今回の研究により、全骨髄細胞の培養上清を活用した新規培養法を開発した。また、この培養法は肝臓再生療法に用いる骨髄MSCの品質を向上させることを確認したため、より治療効果の高い骨髄MSCを用いた再生療法の開発につながる。さらに肝臓以外の線維症に対する治療への応用も可能となる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (46 results)

All 2020 2019 2018 2017 Other

All Journal Article (22 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 19 results,  Open Access: 16 results) Presentation (22 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (2 results)

  • [Journal Article] Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells2020

    • Author(s)
      Miyaji Takashi、Takami Taro、Fujisawa Koichi、Matsumoto Toshihiko、Yamamoto Naoki、Sakaida Isao
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 66 Issue: 3 Pages: 213-223

    • DOI

      10.3164/jcbn.19-125

    • NAID

      130007839286

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of the Effects of Cultured Bone Marrow Mesenchymal Stem Cell Infusion on Hepatocarcinogenesis in Hepatocarcinogenic Mice With Liver Cirrhosis.2019

    • Author(s)
      Matsuura K, Takami T, Maeda M, Hisanaga T, Fujisawa K, Saeki I, Matsumoto T, Hidaka I, Yamamoto N, Sakaida I.
    • Journal Title

      Transplant Proc.

      Volume: 51(3) Issue: 3 Pages: 925-935

    • DOI

      10.1016/j.transproceed.2019.03.011

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canine Liver Fibrosis Model to Assess the Functions of Infused Autologous Bone Marrow-Derived Cells.2019

    • Author(s)
      Takami T, Tani K, Taura Y, Sakaida I.
    • Journal Title

      Methods Mol Biol.

      Volume: 1905 Pages: 201-209

    • DOI

      10.1007/978-1-4939-8961-4_18

    • ISBN
      9781493989607, 9781493989614
    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] NUPR1 acts as a pro-survival factor in human bone marrow-derived mesenchymal stem cells and is induced by the hypoxia mimetic reagent deferoxamine2019

    • Author(s)
      Matsunaga Kazuhito、Fujisawa Koichi、Takami Taro、Burganova Guzel、Sasai Nanami、Matsumoto Toshihiko、Yamamoto Naoki、Sakaida Isao
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 64 Issue: 3 Pages: 209-216

    • DOI

      10.3164/jcbn.18-112

    • NAID

      130007641429

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 核酸医薬品による肝線維化治療2019

    • Author(s)
      高見 太郎、坂井田 功
    • Journal Title

      肝胆膵

      Volume: 79(5) Pages: 861-865

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Liver regeneration therapy through the hepatic artery-infusion of cultured bone marrow cells in a canine liver fibrosis model.2019

    • Author(s)
      Nishimura T, Takami T, Sasaki R, Aibe Y, Matsuda T, Fujisawa K, Matsumoto T, Yamamoto N, Tani K, Taura Y, Sakaida I.
    • Journal Title

      PLoS One.

      Volume: 14(1) Issue: 1 Pages: 234-244

    • DOI

      10.1371/journal.pone.0210588

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Usefulness of Adult Medaka Fish as a Model for the Evaluation of Alcoholic Fatty Liver.2019

    • Author(s)
      Fujisawa K, Takami T, Nagatomo T, Fukui Y, Hoshida H, Saeki I, Matsumoto T, Hidaka I, Yamamoto N, Sakaida I.
    • Journal Title

      Alcohol.

      Volume: 77 Pages: 147-154

    • DOI

      10.1016/j.alcohol.2019.01.005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Liver stiffness measured by transient elastography as predictor of prognoses following portosystemic shunt occlusion.2019

    • Author(s)
      Ishikawa T, Sasaki R, Nishimura T, Matsuda T, Maeda M, Iwamoto T, Saeki I, Hidaka I, Takami T, Sakaida I.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: 34(1) Issue: 1 Pages: 215-223

    • DOI

      10.1111/jgh.14410

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 非代償性肝硬変症に対する自己骨髄細胞を用いた肝臓再生療法2019

    • Author(s)
      高見 太郎、坂井田 功
    • Journal Title

      消化器病学サイエンス

      Volume: 3(1) Pages: 27-31

    • Related Report
      2018 Research-status Report
  • [Journal Article] No Muscle Depletion with High Visceral Fat as a Novel Beneficial Biomarker of Sorafenib for Hepatocellular Carcinoma.2018

    • Author(s)
      Saeki I, Yamasaki T, Maeda M, Kawano R, Hisanaga T, Iwamoto T, Matsumoto T, Hidaka I, Ishikawa T, Takami T, Sakaida I.
    • Journal Title

      Liver Cancer.

      Volume: 7(4) Issue: 4 Pages: 359-371

    • DOI

      10.1159/000487858

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of tolvaptan non-responders and outcomes of tolvaptan treatment of ascites.2018

    • Author(s)
      Iwamoto T, Maeda M, Saeki I, Hidaka I, Tajima K, Ishikawa T, Takami T, Sakaida I.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: - Issue: 7 Pages: 1231-1235

    • DOI

      10.1111/jgh.14524

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy.2018

    • Author(s)
      Saeki I, Yamasaki T, Maeda M, Hisanaga T, Iwamoto T, Fujisawa K, Matsumoto T, Hidaka I, Marumoto Y, Ishikawa T, Yamamoto N, Suehiro Y, Takami T, Sakaida I.
    • Journal Title

      World J Hepatol.

      Volume: 10(9) Issue: 9 Pages: 571-584

    • DOI

      10.4254/wjh.v10.i9.571

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Assessment of high-fat-diet-induced fatty liver in medaka.2018

    • Author(s)
      Fujisawa K, Takami T, Fukui Y, Nagatomo T, Saeki I, Matsumoto T, Hidaka I, Yamamoto N, Okamoto T, Furutani-Seiki M, Sakaida I
    • Journal Title

      Biol Open.

      Volume: 7(11) Pages: 341-347

    • DOI

      10.1242/bio.031534

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growth in vitro and in vivo.2018

    • Author(s)
      Shinoda S, Kaino S, Amano S, Harima H, Matsumoto T, Fujisawa K, Takami T, Yamamoto N, Yamasaki T, Sakaida I.
    • Journal Title

      Oncotarget.

      Volume: 9(47) Issue: 47 Pages: 28434-28444

    • DOI

      10.18632/oncotarget.25421

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparison of patients with hepatic encephalopathy and those with gastric varices before and after balloon-occluded retrograde transvenous obliteration.2018

    • Author(s)
      Ishikawa T, Sasaki R, Nishimura T, Matsuda T, Maeda M, Iwamoto T, Saeki I, Hidaka I, Takami T, Sakaida I.
    • Journal Title

      Hepatol Res.

      Volume: 48(12) Issue: 12 Pages: 1020-1030

    • DOI

      10.1111/hepr.13199

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Blood free-circulating DNA testing by highly sensitive methylation assay to diagnose colorectal neoplasias.2018

    • Author(s)
      Suehiro Y, Hashimoto S, Higaki S, Fujii I, Suzuki C, Hoshida T, Matsumoto T, Yamaoka Y, Takami T, Sakaida I, Yamasaki T.
    • Journal Title

      Oncotarget.

      Volume: 9(24) Issue: 24 Pages: 16974-16987

    • DOI

      10.18632/oncotarget.24768

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells.2018

    • Author(s)
      Fujisawa K, Hara K, Takami T, Okada S, Matsumoto T, Yamamoto N, Sakaida I.
    • Journal Title

      Stem Cell Res Ther.

      Volume: 9(1) Issue: 1 Pages: 93-93

    • DOI

      10.1186/s13287-018-0825-1

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 肝臓再生医療と実践的人材育成 ~培養自己骨髄細胞を用いた低侵襲肝臓再生療法の臨床実施と大学初となる臨床培養士育成コースの開設~2018

    • Author(s)
      高見 太郎、坂井田 功
    • Journal Title

      臨床検査学教育

      Volume: 10(2) Pages: 185-190

    • NAID

      40021658934

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Analysis of Metabolomic Changes in Mesenchymal Stem Cells on Treatment with Desferrioxamine as a Hypoxia Mimetic Compared to Hypoxic Conditions.2018

    • Author(s)
      Fujisawa K, Takami T, Okada S, Hara K, Matsumoto T, Yamamoto N, Yamasaki T, Sakaida I.
    • Journal Title

      Stem Cells

      Volume: 印刷中 Issue: 8 Pages: 1226-1236

    • DOI

      10.1002/stem.2826

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Evaluating effects of L-carnitine on human bone-marrow-derived mesenchymal stem cells.2017

    • Author(s)
      Fujisawa K, Takami T (Corresponding), Fukui Y, Quintanilha LF, Matsumoto T, Yamamoto N, Sakaida I.
    • Journal Title

      Cell Tissue Res

      Volume: 368(2) Issue: 2 Pages: 301-310

    • DOI

      10.1007/s00441-017-2569-0

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells.2017

    • Author(s)
      Matsuda T, Takami T, Sasaki R, Nishimura T, Aibe Y, Paredes BD, Quintanilha LF, Matsumoto T, Ishikawa T, Yamamoto N, Tani K, Terai S, Taura Y, Sakaida I.
    • Journal Title

      Hepatology Communications

      Volume: 1 Issue: 7 Pages: 691-703

    • DOI

      10.1002/hep4.1071

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 自己骨髄細胞による肝臓再生療法の臨床実施とメカニズム解明2017

    • Author(s)
      高見 太郎、藤澤 浩一、坂井田 功
    • Journal Title

      肝胆膵

      Volume: 74(1) Pages: 87-93

    • Related Report
      2017 Research-status Report
  • [Presentation] Resolution of liver fibrosis by autologous bone marrow cell infusion therapy can improve liver function2019

    • Author(s)
      Takami Taro
    • Organizer
      中日先進医療と新薬研究サミット及び成果実業化大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 培養自己骨髄間葉系幹細胞を用いた肝臓再生療法におけるエクソソーム(細胞外小胞)2019

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第26回肝細胞研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 培養自己骨髄間葉系幹細胞肝動脈投与による自己完結型肝硬変再生療法の開発と機序解明2019

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      日本消化器病学会週間
    • Related Report
      2019 Annual Research Report
  • [Presentation] 非代償性肝硬変に対する自己完結型肝硬変再生療法の開発2019

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第43回日本肝臓学会西部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 非代償性肝硬変症に対する自己骨髄間葉系幹細胞を用いた再生療法の開発と展望2019

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第105回日本消化器病学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Our developed liver regeneration therapy using autologous bone marrow derived mesenchymal stem cells for decompensated liver cirrhotic patients2019

    • Author(s)
      Takami Taro, Matsumoto Toshihiko, Sakaida Isao
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 当科における非代償性肝硬変症に対する培養自己骨髄間葉系幹細胞を用いた再生治療2019

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第18回日本再生医療学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 山口大学における臨床培養士養成課程と学会連携2019

    • Author(s)
      高見 太郎、野島 順三、坂井田 功
    • Organizer
      第18回日本再生医療学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Direct infusion of cultured autologous bone marrow-derived mesenchymal stem cells offers higher therapeutic efficacy than conventional peripheral infusion in liver fibrosis animal models2018

    • Author(s)
      Takami T, Sasaki R, Nishimura T, Matsuda T, Fujisawa K, Matsumoto T, Yamamoto N, Sakaida I.
    • Organizer
      6th Annual Midwest Conference on Cell Therapy and Regenerative Medicine
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 抗線維化療法としての自己骨髄細胞を用いた非代償性肝硬変症に対する再生療法の臨床実施と展開2018

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第54回日本肝臓学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 非代償性肝硬変症に対する自己骨髄由来細胞を用いた再生療法の臨床実施2018

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第53回日本アルコール・アディクション医学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 非代償性肝硬変症に対する培養自己骨髄間葉系幹細胞肝動脈投与療法の開発2018

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      JDDW 2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 非代償性肝硬変に対する自己骨髄由来細胞を用いた再生療法の臨床実施2018

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第104回日本消化器病学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] アルコール性肝障害の病態解明のためのエタノール含有水飼育メダカモデルの作出2018

    • Author(s)
      高見 太郎、藤澤 浩一、坂井田 功
    • Organizer
      第53回日本アルコール・アディクション医学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 非代償性肝硬変に対する自己骨髄由来細胞を用いた肝臓再生療法の臨床実施2018

    • Author(s)
      高見 太郎、松本 俊彦、久永 拓郎、藤澤 浩一、石川 剛、坂井田 功
    • Organizer
      第115回日本内科学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] microRNA142-3pによる肝線維化抑制機構の解明2018

    • Author(s)
      松本 俊彦、高見 太郎、坂井田 功
    • Organizer
      第50回日本結合組織学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Our liver regeneration therapies using autologous bone marrow-derived cells for decompensated liver cirrhosis2017

    • Author(s)
      Taro Takami, and Isao Sakaida.
    • Organizer
      第54回日本消化器免疫学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] The development of liver regeneration therapies using autologous bone marrow cells for liver cirrhosis2017

    • Author(s)
      Taro Takami, and Isao Sakaida.
    • Organizer
      ConBio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝硬変症に対する自己骨髄細胞による再生療法の開発状況と展望2017

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第103回日本消化器病学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 非代償性肝硬変症に対する自己骨髄細胞を用いた再生療法の臨床実施と機序解明2017

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      第53回日本肝臓学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 当科における非代償性肝硬変に対する自己骨髄細胞を用いた再生療法2017

    • Author(s)
      高見 太郎、松本 俊彦、坂井田 功
    • Organizer
      JDDW2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝硬変症に対する自己骨髄細胞を用いた再生療法の開発と機序の解明2017

    • Author(s)
      高見 太郎、松本 俊彦、仁志 麻衣子、西村 達朗、佐々木 嶺、相部 祐希、松田 崇史、藤澤 浩一、山本 直樹、坂井田 功
    • Organizer
      第24回肝細胞研究会
    • Related Report
      2017 Research-status Report
  • [Remarks] 山口大学研究推進機構 再生・細胞治療研究センター

    • URL

      http://rcasi.kenkyu.yamaguchi-u.ac.jp/saisei.php

    • Related Report
      2018 Research-status Report
  • [Remarks] 非代償性肝硬変患者に対する培養自己骨髄細胞肝動脈投与療法について

    • URL

      http://www.hosp.yamaguchi-u.ac.jp/news/news/post_252.html

    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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