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Analysis of immunoregulation and mechanism of liver regeneration in cell transplantation

Research Project

Project/Area Number 17K08765
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionSapporo Medical University

Principal Investigator

Ichinohe Norihisa  札幌医科大学, 医学部, 助教 (80452978)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords細胞・組織 / 再生医学 / 肝幹・前駆細胞 / 細胞移植 / 生体組織工学 / 骨髄間葉系細胞 / Extracellular vesicles / 肝再生
Outline of Final Research Achievements

Small hepatocyte-like progenitor cells (SHPCs) transiently appear in rat livers treated with retrorsine (Ret)/70% partial hepatectomy (PH). We reported that transplantation of Thy1+ cells derived from galactosamine-treated liver accelerated the growth of SHPCs in Ret/PH-treated rat livers. Extracellular vesicles (EVs) produced by Thy1+ donor cells activated SHPCs. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we investigated whether BM-MCs could promote the growth of SHPCs as well as hepatic Thy1+ cells. EVs isolated from conditioned medium of cultured BM-MCs were administrated into Ret/PH-treated rat livers, resulting in the growth of SHPCs. Soluble factors contained in EVs were examined and we identified that miRNA146a is the most important factor for enhancing the proliferation of cultured small hepatocytes (SHs). EVs derived from BM-MCs carry miR146a into SHPCs for activating their growth capacity.

Academic Significance and Societal Importance of the Research Achievements

現在、骨髄間葉系幹細胞を用いた脳疾患や脊髄疾患、肝硬変に対する臨床治験が行われている。その治療効果への期待は大きいが、その再生メカニズムはまだよくわかっていない。本研究は骨髄間葉系細胞移植の有効性を基礎的に裏付ける研究であり、細胞移植治療の再生メカニズムの検討から液性因子を同定し、内科的肝再生誘導治療へ繋げることが出来れば、ドナー細胞の確保を必要とせずに薬剤投与による治療が可能になる。また今回の再生誘導因子の同定は、新治療薬の開発のほか、より効率的に肝前駆細胞を体外増幅することが期待でき、肝細胞のドナー細胞不足の解消にも繋がることが期待できる。

Report

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

    (27 results)

All 2020 2019 2018 2017 Other

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results) Presentation (21 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] Self-renewal capability of hepatocytic parental progenitor cells derived from adult rat liver Is maintained long term when cultured on laminin 111 in serum-free medium2020

    • Author(s)
      Kino J, Ichinohe N, Ishii M, Suzuki H, Mizuguchi T, Tanimizu N, Mitaka T
    • Journal Title

      Hepatology Communications

      Volume: 4 Issue: 1 Pages: 21-37

    • DOI

      10.1002/hep4.1442

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Isolation and expansion of rat hepatocytic progenitor cells.2019

    • Author(s)
      Kino J, Ichinohe N, Ishii M, Mitaka T
    • Journal Title

      Methods in Molecular Biology

      Volume: 1905 Pages: 29-41

    • DOI

      10.1007/978-1-4939-8961-4_4

    • ISBN
      9781493989607, 9781493989614
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver.2018

    • Author(s)
      Tanimizu N, Ichinohe N, Mitaka T.
    • Journal Title

      Development

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hepatocytic parental progenitor cells of rat small hepatocytes maintain a self-renewal capability after long-term culture.2017

    • Author(s)
      Ishii M, Kino J, Ichinohe N, Tanimizu N, Ninomiya T, Suzuki H, Mizuguchi T, Hirata K, Mitaka T.
    • Journal Title

      Scientific Reports,

      Volume: 7 Issue: 1 Pages: 46177-46177

    • DOI

      10.1038/srep46177

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 障害肝と骨髄から単離したThy1陽性間葉系細胞による肝再生メカニズムの比較検討2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第108回日本病理学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 障害肝由来Thy1陽性間葉系細胞と骨髄間葉系細胞のエクソソームによる肝前駆細胞誘導機序2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第26回肝細胞研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肝細胞の前駆細胞:増殖と活性化2019

    • Author(s)
      三高 俊広, 谷水 直樹, 市戸 義久
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 成熟ラット肝細胞由来肝前駆細胞のself-renewal能の維持機構2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肝前駆細胞と細胞移植2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第51回日本臨床分子形態学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 骨髄間葉系細胞移植により誘導されたSHPCsの遺伝子発現解析2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第31回日本肝臓医生物学研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 障害肝と骨髄から単離したThy1陽性間葉系細胞による肝前駆細胞増幅機構の比較検討2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広.
    • Organizer
      第52回北海道病理談話会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Transplantation of bone marrow mesenchymal cells enhance liver regeneration by secreted extracellular vesicles directly activating of hepatic progenitor cells.2019

    • Author(s)
      Norihisa Ichinohe, Naoki Tanimizu, Toshihiro Mitaka
    • Organizer
      COLD SPRING HARBOR ASIA CONFERENCES. LIVER, BIOLOGY, DISEASES & CANCER
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 障害肝由来Thy1陽性細胞と骨髄間葉系細胞移植による肝再生メカニズムの比較検討2019

    • Author(s)
      市戸義久,谷水直樹,三高俊広
    • Organizer
      第18回 日本再生医療学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 骨髄間葉系細胞由来液性因子による内在性肝前駆細胞増殖促進機構の解析2018

    • Author(s)
      市戸義久, 石井雅之, 谷水直樹, 三高俊広
    • Organizer
      第54回日本肝臓学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 骨髄間葉系細胞移植による肝再生促進機構の解析2018

    • Author(s)
      市戸義久, 石井雅之, 谷水直樹, 三高俊広
    • Organizer
      第107回日本病理学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 障害肝由来Thy1陽性間葉系細胞による肝再生メカニズムの解析2018

    • Author(s)
      市戸義久,谷水直樹, 三高俊広
    • Organizer
      第25回肝細胞研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] 障害肝由来Thy1陽性細胞と骨髄間葉系細胞によるSHPCs増殖促進機構の比較検討2018

    • Author(s)
      市戸義久,谷水直樹,三高俊広
    • Organizer
      第29回 日本肝臓医生物学研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] 継代培養可能な肝前駆細胞の分離と細胞移植ソースの可能性2017

    • Author(s)
      市戸義久、石井雅之、木野潤一、谷水直樹、三高俊広.
    • Organizer
      第106回日本病理学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 継代培養可能な肝前駆細胞の創製と特性解析2017

    • Author(s)
      市戸義久、石井雅之、谷水直樹、水口徹、三高俊広.
    • Organizer
      第53回日本肝臓学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 細胞外マトリクス上における成体ラット小型肝細胞由来CD44陽性細胞の機能解析2017

    • Author(s)
      木野潤一、石井雅之、市戸義久、谷水直樹、水口徹、三高俊広
    • Organizer
      第24回肝細胞研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 骨髄間葉系細胞由来液性因子による肝再生機構の解析2017

    • Author(s)
      市戸義久、石井雅之、木野潤一、谷水直樹、三高俊広.
    • Organizer
      第24回肝細胞研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝細胞増幅方法の確立と肝細胞移植による肝再生2017

    • Author(s)
      三高俊広、市戸義久、谷水直樹.
    • Organizer
      第21回日本肝臓学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] 骨髄間葉系細胞による肝再生促進機構の解析2017

    • Author(s)
      市戸義久、石井雅之、谷水直樹、三高俊広.
    • Organizer
      第50回北海道病理談話会
    • Related Report
      2017 Research-status Report
  • [Presentation] 骨髄間葉系細胞移植による内在性肝前駆細胞増殖促進機構の解析2017

    • Author(s)
      市戸義久、石井雅之、谷水直樹、三高俊広.
    • Organizer
      第17回日本再生医療学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝機能向上を目指した肝前駆細胞の培養条件の検討2017

    • Author(s)
      谷水直樹、市戸義久、三高俊広.
    • Organizer
      第17回日本再生医療学会総会
    • Related Report
      2017 Research-status Report
  • [Remarks] 札幌医科大学フロンティア医学研究所組織再生学部門

    • URL

      https://www.smu-tisdevreg.jp

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
  • [Remarks] 札幌医科大学フロンティア医学研究所組織再生学部門

    • URL

      http://web.sapmed.ac.jp/canpath/Tissue_Development_%26_Regeneration/Tissue_Devel%26Regen.html

    • Related Report
      2017 Research-status Report

URL: 

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

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