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Development of tendon/ligament injury treatment based on the understanding of its molecular mechanism

Research Project

Project/Area Number 20H03805
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionHiroshima University

Principal Investigator

Adachi Nobuo  広島大学, 医系科学研究科(医), 教授 (30294383)

Co-Investigator(Kenkyū-buntansha) 味八木 茂  広島大学, 病院(医), 講師 (10392490)
亀井 直輔  広島大学, 医系科学研究科(医), 准教授 (70444685)
石川 正和  香川大学, 医学部, 教授 (60372158)
中佐 智幸  広島大学, 病院(医), 講師 (60467769)
宿南 知佐  広島大学, 医系科学研究科(歯), 教授 (60303905)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2020: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords腱・靭帯 / microRNA / 間葉系幹細胞 / 細胞外小胞 / 腱修復 / 腱発生 / エクソソーム
Outline of Research at the Start

腱や靭帯は、分子生物学的な情報は他の運動器に比べて極めて少なく、その治癒を促進する治療法は未だ開発されていない。本研究は、microRNA(miRNA)生成に重要なプロセッシング酵素Dicerを腱・靭帯特異的にノックアウトしたマウスの解析を行い、腱・靭帯におけるDicerの機能解析と腱・靭帯特異的miRNAを探索する。また、同定したmiRNAとMSC由来エクソソームを組合せた新たな治療法の開発を目指すものである。

Outline of Final Research Achievements

In this study, we focused on the functions of microRNA (miRNA) in tendons and ligaments, and investigated the effect of miRNA-containing extracellular vesicles on promoting tendon repair. Tendon- and ligament-specific Dicer knockout mice exhibited hypoplasia of tendon due to decreased expression of related genes in tendons and ligaments. Then, we identified a highly expressed miRNA in tendon tissue, and its over-introduction into tendon progenitor cells induced the expression of tendon-related genes. In Achilles tendon injury models, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) inhibited calcification and adhesion during the tendon healing, promoted their repair. Furthermore, the glycan expressed on the surface of MSC-EVs and it was shown that it is possible to evaluate the therapeutic effect (quality) based on the glycan expression pattern.

Academic Significance and Societal Importance of the Research Achievements

腱や靭帯は、運動機能の中心的役割を担うが、分子生物学的な情報は他の運動器に比べて極めて少なく、その治癒を促進する治療法は未だ開発されていない。本研究は、遺伝子発現制御ネットワークに重要な因子であるmiRNAの腱・靭帯における機能を明らかにし、腱組織で高発現しているmiRNAを同定した。そして、miRNAを含むMSC-EVによる腱修復促進効果を明らかにするだけでなく、MSC-EV表面に発現している糖鎖発現パターンによるMSC-EVの質(治療効果)を評価できる可能性を提唱した。よって、目的miRNAを豊富に含んだMSC-EV投与による腱損傷における新たな治療法の開発につながる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (4 results)

All 2022 2021

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

  • [Journal Article] Tendon-Specific Dicer Deficient Mice Exhibit Hypoplastic Tendon Through the Downregulation of Tendon-Related Genes and MicroRNAs2022

    • Author(s)
      Omoto Takenori、Yimiti Dilimulati、Sanada Yohei、Toriyama Minoru、Ding Chenyang、Hayashi Yuta、Ikuta Yasunari、Nakasa Tomoyuki、Ishikawa Masakazu、Sano Masayuki、Lee Minjung、Akimoto Takayuki、Shukunami Chisa、Miyaki Shigeru、Adachi Nobuo
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 10 Pages: 898428-898428

    • DOI

      10.3389/fcell.2022.898428

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The therapeutic capacity of bone marrow MSC-derived extracellular vesicles in Achilles tendon healing is passage-dependent and indicated by specific glycans.2022

    • Author(s)
      Hayashi Y, Yimiti D, Sanada Y, Ding C, Omoto T, Ogura T, Nakasa T, Ishikawa M, Hiemori K, Tateno H, Miyaki S, Adachi N.
    • Journal Title

      FEBS Lett.

      Volume: 596(8) Issue: 8 Pages: 1047-1058

    • DOI

      10.1002/1873-3468.14333

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 腱修復時における異所性骨化に対するレチノイン酸受容体アゴニストの治療効果2022

    • Author(s)
      Dilimulati Yimiti、味八木茂、内部健太、中佐智幸、石川正和、安達伸生
    • Organizer
      第37回日本整形外科学会基礎学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] RNAプロセッシング酵素Dicerは腱の発生・成熟および損傷修復過程に関与する2021

    • Author(s)
      大本武児、味八木茂、眞田洋平、中佐智幸、石川正和、亀井直輔、宿南知佐、安達伸生
    • Organizer
      第36回日本整形外科学会基礎学術集会
    • Related Report
      2021 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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