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Elucidation of the origin of blood coagulation factor VIII-producing cells for the development of new hemophilia treatment

Research Project

Project/Area Number 18K08370
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionJichi Medical University

Principal Investigator

Ohmori Tsukasa  自治医科大学, 医学部, 教授 (70382843)

Co-Investigator(Kenkyū-buntansha) 早川 盛禎  自治医科大学, 医学部, 講師 (30326847)
長尾 恭光  自治医科大学, 医学部, 准教授 (80303874)
鴨下 信彦  自治医科大学, 医学部, 講師 (90302603)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords血液凝固第VIII因子 / 血友病A / 再生医療 / 遺伝子治療 / 肝臓類洞内皮細胞 / 血友病 / 第VIII因子
Outline of Final Research Achievements

Since coagulation factors are produced by hepatocytes, the coagulation factors in blood are decreased in cirrhosis. However, blood coagulation factor VIII (FVIII) is rather elevated. Here, we attempted to identify FVIII-producing cells by using knock-in mice in which FVIII-producing cells were observed as EGFP-expressing cells. EGFP-expressing FVIII-producing cells were found only in hepatic sinusoids. FVIII-producing cells had characteristics of lymphatic endothelial cells, including CD146, CD31, and Lyve1, but also expressed the platelet marker Clec-2. FVIII-producing cells in the fetal liver were observed from E12.5 and increased with development to the same level as in adult mice at birth. FVIII-conditional deficient mice showed reduced FVIII levels when crossed with Lyve1-Cre mice. Finally, the AAV vector could efficiently express the reporter gene in FVIII-producing cells.

Academic Significance and Societal Importance of the Research Achievements

これまでFVIIIの産生細胞について一貫した報告はなかった。本研究でFVIIIは臓器の中でも肝臓のみに発現し、かつ類洞内皮細胞の一部がFVIII産生を担っていることを明らかとした。さらに、FVIII産生細胞はリンパ管内皮細胞と同様の性質を有するが、特徴的な表面マーカーとして血小板に存在するClec-2を同定した。さらに、FVIII産生細胞の分化過程を明らかにし、発現が上昇する分子からFVIII産生細胞に遺伝子導入が可能なプロモーター領域を見出した。これらの研究成果は、FVIIIが遺伝的に欠損する血友病Aに対する新たな遺伝子治療、細胞治療に結びつくことが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (35 results)

All 2021 2020 2019 2018

All Journal Article (16 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 14 results,  Open Access: 2 results) Presentation (15 results) (of which Int'l Joint Research: 2 results,  Invited: 12 results) Book (4 results)

  • [Journal Article] Non-viral ex vivo genome-editing in mouse bona fide hematopoietic stem cells with CRISPR/Cas9.2021

    • Author(s)
      Byambaa S, Uosaki H, Ohmori T, Hara H, Endo H, Nureki O, Hanazono Y.
    • Journal Title

      Mol Ther Methods Clin Dev

      Volume: 20 Pages: 451-462

    • DOI

      10.1016/j.omtm.2021.01.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ASC regulates platelet activation and contributes to thrombus formation independent of NLRP3 inflammasome2020

    • Author(s)
      Watanabe Sachiko、Usui-Kawanishi Fumitake、Komada Takanori、Karasawa Tadayoshi、Kamata Ryo、Yamada Naoya、Kimura Hiroaki、Dezaki Katsuya、Ohmori Tsukasa、Takahashi Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 531 Issue: 2 Pages: 125-132

    • DOI

      10.1016/j.bbrc.2020.07.063

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hemophilia gene therapy?New country initiatives2020

    • Author(s)
      Reiss Ulrike M.、Zhang Lei、Ohmori Tsukasa
    • Journal Title

      Haemophilia

      Volume: 27 Issue: S3 Pages: 132-141

    • DOI

      10.1111/hae.14080

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Successful treatment of hepatocellular carcinoma by laparoscopic radiofrequency ablation in a patient with hemophilia A2020

    • Author(s)
      Goka Rie、Morimoto Naoki、Miura Kouichi、Watanabe Shunji、Takaoka Yoshinari、Nomoto Hiroaki、Tsukui Mamiko、Fujieda Takeshi、Maeda Hiroshi、Sato Naoto、Ohmori Tsukasa、Isoda Norio、Yamamoto Hironori
    • Journal Title

      Clinical Journal of Gastroenterology

      Volume: 13 Issue: 5 Pages: 907-913

    • DOI

      10.1007/s12328-020-01133-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Altered behavior in mice overexpressing soluble ST22020

    • Author(s)
      Motoshi Kikuchi, Kenkichi Takase, Morisada Hayakawa, Hiroko Hayakawa, Shin-Ichi Tominaga, Tsukasa Ohmori
    • Journal Title

      Molecular Brain

      Volume: 13 Issue: 1 Pages: 74-84

    • DOI

      10.1186/s13041-020-00606-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a Unique T Cell Receptor Gene-Transferred Tax-Redirected T Cell Immunotherapy for Adult T Cell Leukemia2020

    • Author(s)
      Kawamura Koji、Tanaka Yukie、Nakasone Hideki、Ishihara Yuko、Kako Shinichi、Kobayashi Seiichiro、Tanaka Yuetsu、Ohmori Tsukasa、Uchimaru Kaoru、Okamoto Sachiko、Mineno Junichi、Shiku Hiroshi、Nishimura Satoshi、Kanda Yoshinobu
    • Journal Title

      Biology of Blood and Marrow Transplantation

      Volume: 26 Issue: 8 Pages: 1377-1385

    • DOI

      10.1016/j.bbmt.2020.04.006

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deletion of inflammasome adaptor protein ASC enhances functional recovery after spinal cord injury in mice2020

    • Author(s)
      Shiraishi Yasuyuki、Kimura Atsushi、Kimura Hiroaki、Ohmori Tsukasa、Takahashi Masafumi、Takeshita Katsushi
    • Journal Title

      Journal of Orthopaedic Science

      Volume: 20 Issue: 3 Pages: 30124-30124

    • DOI

      10.1016/j.jos.2020.04.006

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hemophilia gene therapy; New country initiatives2020

    • Author(s)
      Reiss UM, Zhang L, Ohmori T
    • Journal Title

      Haemophilia

      Volume: in press

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Establishment of a megakaryoblastic cell line for conventional assessment of platelet calcium signaling2020

    • Author(s)
      Saito H, Hayakawa M, Kamoshita N, Yasumoto A, Suzuki-Inoue K, Yatomi Y, Ohmori T
    • Journal Title

      Int J Hematol

      Volume: in press Issue: 6 Pages: 786-794

    • DOI

      10.1007/s12185-020-02853-6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Induction of IκBζ augments cytokine and chemokine production by IL-33 in mast cells.2020

    • Author(s)
      Ohto-Ozaki H, Hayakawa M, Kamoshita N, Maruyama T, Tominaga S-I, Ohmori T
    • Journal Title

      J Immunol.

      Volume: 204 Issue: 8 Pages: 2033-2042

    • DOI

      10.4049/jimmunol.1900315

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Utility of microminipigs for evaluating liver-mediated gene expression in the presence of neutralizing antibody against vector capsid2020

    • Author(s)
      Watano R, Ohmori T, Hishikawa S, Sakata A, and Mizukami H.
    • Journal Title

      Gene Therapy

      Volume: in press Issue: 9 Pages: 427-434

    • DOI

      10.1038/s41434-020-0125-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 特集 ゲノム編集技術の基礎と応用 5.ゲノム編集とウイルスベクター2018

    • Author(s)
      大森司
    • Journal Title

      血液フロンティア

      Volume: 28 Issue: 7 Pages: 1053-1059

    • DOI

      10.20837/52018071053

    • ISSN
      1344-6940
    • Year and Date
      2018-06-30
    • Related Report
      2018 Research-status Report
  • [Journal Article] Advances in gene therapy for hemophilia: basis, current status, and future perspectives2018

    • Author(s)
      Ohmori Tsukasa
    • Journal Title

      International Journal of Hematology

      Volume: E-pub Issue: 1 Pages: 31-41

    • DOI

      10.1007/s12185-018-2513-4

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Safety of intra-articular transplantation of lentivirally transduced mesenchymal stromal cells for haemophilic arthropathy in a non-human primate2018

    • Author(s)
      Ohmori Tsukasa、Mizukami Hiroaki、Katakai Yuko、Kawai Sho、Nakamura Hitoyasu、Inoue Makoto、Shu Tsugumine、Sugimoto Hideharu、Sakata Yoichi
    • Journal Title

      International Journal of Hematology

      Volume: 108 Issue: 3 Pages: 239-245

    • DOI

      10.1007/s12185-018-2465-8

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of gene therapy for hemophilia: current states and future perspectives2018

    • Author(s)
      大森 司
    • Journal Title

      Rinsho Ketsueki

      Volume: 59 Issue: 10 Pages: 2238-2246

    • DOI

      10.11406/rinketsu.59.2238

    • NAID

      130007496694

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] 血友病の遺伝子治療2018

    • Author(s)
      大森 司
    • Journal Title

      Japanese Journal of Thrombosis and Hemostasis

      Volume: 29 Issue: 6 Pages: 760-764

    • DOI

      10.2491/jjsth.29.760

    • NAID

      130007530651

    • ISSN
      0915-7441, 1880-8808
    • Related Report
      2018 Research-status Report
  • [Presentation] 血友病に対する遺伝子治療の現状2021

    • Author(s)
      大森 司
    • Organizer
      第15回日本血栓止血学会学術標準化委員会シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] アデノ随伴ウイルスベクターをも用いた血友病に対する遺伝子治療2021

    • Author(s)
      大森 司
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 血友病の病態解明と治療への応用2020

    • Author(s)
      大森 司
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] いちから学ぶ出血傾向2020

    • Author(s)
      大森 司
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] カニクイザルを用いた血友病性関節症に対する凝固因子発現間葉系幹細胞の安全性評価2019

    • Author(s)
      大森 司,水上 浩明,片貝 祐子,川合 創,中村 仁康,井上 誠,朱 亜峰,杉本 英治,坂田 洋一
    • Organizer
      第41回 日本血栓止血学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Adeno-associated virus vector based on serotype 3 represents an alternative serotype for hemophilia gene therapy2019

    • Author(s)
      Ohmori, T., Mizukami, H., Hishikawa, S., Nakamura, H., Katakai, Y., Muramatsu, S., Ozawa, K., and Sakata, Y.
    • Organizer
      Congress The International Society on Thrombosis and Haemostasis
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 血友病に対する遺伝子治療とゲノム編集治療2019

    • Author(s)
      大森 司
    • Organizer
      BioJapan2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 血友病に対する遺伝子治療とゲノム編集治療の進歩2019

    • Author(s)
      大森 司
    • Organizer
      第61回日本小児血液・がん学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ゲノム編集技術による疾患治療戦略2018

    • Author(s)
      大森 司
    • Organizer
      日本小児神経学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 血友病に対するin vivoゲノム編集治療2018

    • Author(s)
      大森 司
    • Organizer
      第3回日本ゲノム編集学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] CRISPR/Cas9-mediated Genome Editing for Hemophilia B by AAV vector2018

    • Author(s)
      Tsukasa Ohmori
    • Organizer
      The 10th Congress of Asia Pacific Society on Thrombosis and Hemostasis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Development of Genome editing treatment for Hemophilia2018

    • Author(s)
      大森 司
    • Organizer
      The 24th Annual Meeting of Japan Society of Gene and Cell Therapy
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 血友病に対する遺伝子治療の展望2018

    • Author(s)
      大森 司
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] ゲノム編集による血友病治療の試み2018

    • Author(s)
      大森 司
    • Organizer
      創薬薬理フォーラム第26回シンポジウム
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 血友病遺伝子治療の現状と展望2018

    • Author(s)
      大森 司
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Book] 決定版 ウイルスベクターによる遺伝子導入実験ガイド2020

    • Author(s)
      平井 宏和、日置 寛之、小林 和人
    • Total Pages
      285
    • Publisher
      羊土社
    • ISBN
      9784758122474
    • Related Report
      2020 Annual Research Report
  • [Book] EBM血液疾患の治療2021-20222020

    • Author(s)
      金倉 譲、木崎昌宏、鈴木律朗、神田善伸、大森 司、山崎宏人
    • Total Pages
      637
    • Publisher
      中外医学社
    • Related Report
      2020 Annual Research Report
  • [Book] 血液疾患最新の治療2020-20222019

    • Author(s)
      大森 司
    • Total Pages
      390
    • Publisher
      南江堂
    • ISBN
      9784524249787
    • Related Report
      2019 Research-status Report
  • [Book] 臨床に直結する血栓止血学2018

    • Author(s)
      大森 司
    • Total Pages
      9
    • Publisher
      中外医学社
    • ISBN
      4498125797
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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