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Novel therapies development of multiple myeloma using engineering exosomes derived from bone marrow stromal cells

Research Project

Project/Area Number 16K07183
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor therapeutics
Research InstitutionTokyo Medical University

Principal Investigator

Ohyashiki Junko  東京医科大学, 医学部, 教授 (20191950)

Co-Investigator(Kenkyū-buntansha) 梅津 知宏  東京医科大学, 医学部, 講師 (40385547)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsエクソソーム / 骨髄間質細胞 / 多発性骨髄腫 / 腫瘍血管新生 / miRNA / 加齢
Outline of Final Research Achievements

Bone marrow stromal cells (BMSCs) and their exosomes are a promising area of cancer therapy. Here, we investigated therapeutic effects of BMSC exosomes derived from young and elderly donors using in vivo models of bone marrow in multiple myeloma (MM). We found that the donor’s age decides senescent changes in BMSC, and exosomes derived from young BMSCs could block MM cell-induced angiogenesis in Matrigel plug. We also noted young BMSC-specific exosomal miRNA, such as miR-340. Of note is that the anti-angiogenic effect was potentiated by engineering exosomes of elderly BMSCs; exosomes are directly transfected with miR-340, resulting in exosome rejuvenation.
Our results suggest that the BMSC exosomes is able to transfer the miRNAs, which have the ability to inhibit angiogenesis and progression of MM. The present study provides a new insight toward exosome-based cancer therapy by engineering exosomes of BMSCs.

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫の骨髄微小環境制御を主眼としたアプローチはSDF-1やCXCR4などの液性因子を中心に展開されている。本研究では人工的にmiRNAを直接エクソソームに添加し効果を発揮させるという我々が開発した革新的手法を用いている。また、抗原性が少なく細胞治療としての有用性が検証されているMSCに着眼し、細胞治療の発展型ともいえる核酸医薬研究である。抗腫瘍血管新生効果の高い「機能強化型エクソソーム」を安定的に供給する事も可能になる。本研究は技術的にも革新的がん治療として注目の領域であると同時に高齢化社会でますます患者数の増加が見込まれる多発性骨髄腫患者のADL向上につながり社会的貢献度は大きい。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (31 results)

All 2019 2018 2017 2016

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (19 results) (of which Int'l Joint Research: 12 results,  Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Maintenance 5-azacytidine therapy by MRD monitoring after allogeneic HSCT in myeloid/lymphoid neoplasms with FGFR1 rearrangement.2019

    • Author(s)
      Katagiri S, Umezu T, Azuma K, Kobayashi C, Akahane D, Suguro T, Furuya N, Fujimoto H, Nakamura N, Ohyashiki JH, Ohyashiki K.
    • Journal Title

      Bone Marrow Transplant.

      Volume: - Issue: 7 Pages: 1148-1150

    • DOI

      10.1038/s41409-019-0436-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chromatin Regulation by HP1γ Contributes to Survival of 5-Azacytidine-Resistant Cells.2018

    • Author(s)
      Imanishi S, Umezu T, Kobayashi C, Ohta T, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Front Pharmacol.

      Volume: 9 Pages: 1166-1166

    • DOI

      10.3389/fphar.2018.01166

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exosomal miRNA Signatures for Late-Onset Acute Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation.2018

    • Author(s)
      Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K.
    • Journal Title

      Int J Mol Sci.

      Volume: 19(9) Issue: 9 Pages: 2493-2493

    • DOI

      10.3390/ijms19092493

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular vesicle (EV)- mediated cell-cell communication in hematologic neoplasms2018

    • Author(s)
      Ohyashiki JH, Umezu T, Ohyashiki K
    • Journal Title

      Philosophical Transactions of the Royal Society B: Biological Sciences

      Volume: 373 Issue: 1737 Pages: 1737-1737

    • DOI

      10.1098/rstb.2016.0484

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hidden FLT3-D835Y clone in FLT3-ITD-positive acute myeloid leukemia that evolved into very late relapse with T-lymphoblastic leukemia2017

    • Author(s)
      Katagiri S, Umezu T, Asano M, Akahane D, Azuma K, Makishima H, Yoshida K, Watatani Y, Chiba K, Miyano S, Ogawa S, Ohyashiki JH, Ohyashiki K
    • Journal Title

      Leukemia and Lymphoma

      Volume: 3 Issue: 6 Pages: 1-4

    • DOI

      10.1080/10428194.2017.1382696

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Upregulated exosomal miRNA-140-3p in CML patients with musculoskeletal pain associated with discontinuation of tyrosine kinase inhibitors2017

    • Author(s)
      Asano M, Umezu T, Katagiri S, Kobayashi C, Tauchi T, Gotoh M, Ando K, Okabe S, Ohyashiki JH, Ohyashiki K
    • Journal Title

      Int J Hematol

      Volume: 105(4) Issue: 4 Pages: 419-422

    • DOI

      10.1007/s12185-017-2199-z

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myeloma-related angiogenesis.2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Kobayashi C, Yoshizawa S, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Blood Adv

      Volume: 1(13) Issue: 13 Pages: 812-823

    • DOI

      10.1182/bloodadvances.2016003251

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells.2017

    • Author(s)
      Imanishi S, Takahashi R, Katagiri S, Kobayashi C, Umezu T, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Oncotarget

      Volume: 8(41) Issue: 41 Pages: 69906-69915

    • DOI

      10.18632/oncotarget.19436

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic variations of bone marrow mesenchymal stromal cells derived from acute leukemia and myelodysplastic syndrome by targeted deep sequencing.2017

    • Author(s)
      Azuma K, Umezu T, Imanishi S, Asano M, Yoshizawa S, Katagiri S, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Leuk Res

      Volume: 62 Pages: 23-28

    • DOI

      10.1016/j.leukres.2017.09.008

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Extracellular vesicle-mediated cell-cell communication in haematological neoplasms2017

    • Author(s)
      Ohyashiki JH, Umezu T, Ohyashiki K.
    • Journal Title

      Philosophical Transactions B of the Royal Society

      Volume: 印刷中

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Exosomes promote bone marrow angiogenesis in hematologic neoplasia: the role of hypoxia.2016

    • Author(s)
      Ohyashiki JH, Umezu T, Ohyashiki K
    • Journal Title

      Curr Opin Hematol

      Volume: 23(3) Issue: 3 Pages: 268-273

    • DOI

      10.1097/moh.0000000000000235

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Characterization of novel bona marrow stromal cells from healthy donors.2018

    • Author(s)
      Umezu T, Gladkova N, Imanishi S, Ohyashiki K, Ohyashiki JH
    • Organizer
      第36回ヒト細胞学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Sequential analysis of clonal evolution by targeted deep sequencing in therapy-related myeloid neoplasm.2018

    • Author(s)
      Katagiri S, Azuma K, Saito Y, Yoshizawa S, Akahane D, Fujimoto H, Ito Y, Umezu T, Ohyashiki JH, Ohyashiki K
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Extracellular vesicle-mediated miRNA transfer enhances growth and survival of multiple myeloma.2018

    • Author(s)
      Umezu T, Imanishi, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 5-azacytidine targets chromatin regulation through piRNA pathway.2018

    • Author(s)
      Imanishi S, Azuma K, Umezu T, Kawana C, Ohyashiki K, Ohyashiki JH
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The role of extracellular vesicle-mediated miR-10a transfer in bone marrow microenvironment of patients with multiple myeloma.2018

    • Author(s)
      Umezu T, Ohyashiki K, Ohyashiki JH
    • Organizer
      International Society for Extracellular Vesicles 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Bone marrow mesenchymal stromal cells from healthy donors secrete anti-angiogenic EVs as well as soluble factors having growth inhibitory effect in MM.2018

    • Author(s)
      Umezu T, Imanishi S, Gladkova N*, Ohyashiki K, Ohyashiki JH
    • Organizer
      European Hematology Association 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of extracellular vesicles-mediated angiogensis in hematologic neoplasias2017

    • Author(s)
      Ohyashiki JH
    • Organizer
      Royal Society meeting entitled ‘Extracellular Vesicles in the Tumor Microenvironment’
    • Place of Presentation
      London (UK)
    • Year and Date
      2017-01-23
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Replenishing exosomes from older bone marrow stromal cells by miR-340 inhibits myeloma-related angiogenesis.2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH:
    • Organizer
      The Royal Society Scientific Meeting 2017 “Extracellular vesicles and the tumor microenvironment”
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Extracellular vesicles (EVs) released by bone marrow stromal cells show a distinct miRNA profile in high-risk MDS patients.2017

    • Author(s)
      Ohyashiki K, Saitoh Y, Imanishi S, Umezu T, Yoshizawa S, Asano M, Fujimoto H, Akahane D, Kobayashi C, Ohyashiki JH:
    • Organizer
      The 14th International Symposium on Myelodysplastic Syndromes (MDS2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Telomeric repeat-containing RNA (TERRA) in MDS: Utility of cell-free TERRA packaged in extracellular vesicles.2017

    • Author(s)
      Ohyashiki JH, Umezu T, Kobayashi C, Imanishi S, Asano M, Ohyashiki K:
    • Organizer
      The 14th International Symposium on Myelodysplastic Syndromes (MDS2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells.2017

    • Author(s)
      Imanishi S, Takahashi R, Katagiri S, Umezu T, Yoshizawa S, Kobayashi C, Ohyashiki K, Ohyashiki JH:
    • Organizer
      The 14th International Symposium on Myelodysplastic Syndromes (MDS2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A role of exosomal miR-10a in bone marrow stromal cells obtained from patients with multiple myeloma.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      6th Annual Meeting of International Society for Extracellular Vesicles (ISEV2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] miRNA profiling of circulating extracellular vesicles in CML patients with musculoskeletal pain associated with discontinuation of tyrosine kinase inhibitors.2017

    • Author(s)
      Ohyashiki K, Asano M, Umezu T, Katagiri S, Kobayashi C, Tauchi T, Gotoh M, Ando K, Okabe S, Ohyashiki JH:
    • Organizer
      22nd Congress of European Hematology Association (EHA2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inhibition of extracellular vesicle secretion induces apoptosis of bone marrow stromal cells: Towards soil-targeted therapy in multiple myeloma.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyahsiki K, Ohyashiki JH
    • Organizer
      22nd Congress of European Hematology Association (EHA2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A statistical integrative analysis method for small size expression data of microRNAs and genes.2017

    • Author(s)
      Ohki T, Umezu T, Ohyahsiki JH, Fukuoka Y
    • Organizer
      39th International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE EMBC2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cross-talk mediated by bone marrow stromal cells-derived extracellular vesicles.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      Tokyo Medical University, Institute of Medical Science, 1st International Symposium “Role of Aging and Cancer”
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inhibition of extracellular vesicle secretion induces apoptosis of bone marrow stromal cells derived from multiple myeloma patients.2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      The 76th Annual Meeting of Japanese Cancer Association (JCA2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] Altered exosomal miRNA expression of late onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation.2017

    • Author(s)
      Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K
    • Organizer
      The 79th Annual Meeting of Japanese Society of Hematology (JSH2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] Anti-angiogenic effect of normal bone marrow stromal cell-derived exosomes rejuvenated by miR-340.2016

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      The 78th Annual Meeting of Japanese Society of Hematology
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] がんの罹患の可能性の試験方法およびそれに用いる試験試薬2017

    • Inventor(s)
      大屋敷純子、梅津 知宏
    • Industrial Property Rights Holder
      学校法人 東京医科大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-083898
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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