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Intervertebral disc regeneration and transcriptional control of nucleus pulpous progenitor cells by in silico pharmacogenesis and iPS technology

Research Project

Project/Area Number 16H05456
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionTokai University

Principal Investigator

SAKAI Daisuke  東海大学, 医学部, 准教授 (10408007)

Co-Investigator(Kenkyū-buntansha) 檜山 明彦  東海大学, 医学部, 講師 (00514382)
平山 令明  東海大学, 先進生命科学研究所, 教授 (70238393)
升井 伸治  京都府立医科大学, 医学(系)研究科(研究院), 特任准教授 (20342850)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Keywords椎間板変性 / 再生医療 / 髄核細胞 / 椎間板再生 / 腰痛 / 転写因子 / 椎間板 / iPS技術 / インシリコ創薬 / iPS細胞 / 移植・再生医療 / 再生医学 / 同種細胞移植 / 凍結保存 / 整形外科学 / 脊椎脊髄病学 / iPS細胞技術 / 創薬
Outline of Final Research Achievements

Low back pain is considered the major cause of disability worldwide and is linked to a significant socio-economic burden on health care and social security systems. Intervertebral disc disorder is a major cause of low back pain, and a method for artificially deriving intervertebral disc cells has not yet been established. A method for artificially deriving intervertebral disc cells has not been established yet. We set out to search for a method to directly reprogram the intervertebral disc into nucleus pulposus cells. Therefore, we first attempted a comprehensive screening approach to identify transcription factors essential and highly related to the nucleus pulposus cell phenotype. We applied microarray, iPSC interference assay, siRNA assay, gene upregulation assay, and direct cell reprogramming. Combination of 3 strong transcription factors that induces prominent expression of nucleus pulposus cell markers were identified and patented.

Academic Significance and Societal Importance of the Research Achievements

現在、腰痛の新規治療法として、細胞移植を中心とした技術が検討されているが、本研究の結果は椎間板細胞製品のコストダウン、有効性の向上へ寄与できる技術となったほか、未だ発見されていない技術であるため科学的にも意味が大きい研究成果であると考える。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (34 results)

All 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (15 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 15 results,  Open Access: 11 results) Presentation (9 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results) Remarks (1 results) Patent(Industrial Property Rights) (6 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] AO Research Institute(スイス)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] アイルランド国立大学ゴールウェイ校(アイルランド)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] ベルン大学/AO research Institute(スイス)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Minimal Sustainability of Dedifferentiation by ROCK Inhibitor on Rat Nucleus Pulposus Cells In Vitro2019

    • Author(s)
      Nukaga Tadashi、Sakai Daisuke、Schol Jordy、Suyama Kaori、Nakai Tomoko、Hiyama Akihiko、Watanabe Masahiko
    • Journal Title

      Spine Surgery and Related Research

      Volume: 3 Issue: 4 Pages: 385-391

    • DOI

      10.22603/ssrr.2019-0019

    • NAID

      130007734403

    • ISSN
      2432-261X
    • Year and Date
      2019-10-27
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mesenchymal Stem Cell Homing Into Intervertebral Discs Enhances the Tie2-positive Progenitor Cell Population, Prevents Cell Death, and Induces a Proliferative Response2019

    • Author(s)
      Wangler Sebastian、Peroglio Marianna、Menzel Ursula、Benneker Lorin M.、Haglund Lisbet、Sakai Daisuke、Alini Mauro、Grad Sibylle
    • Journal Title

      SPINE

      Volume: 44 Issue: 23 Pages: 1613-1622

    • DOI

      10.1097/brs.0000000000003150

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Annulus fibrosus cell sheets limit disc degeneration in a rat annulus fibrosus injury model2019

    • Author(s)
      Nukaga Tadashi、Sakai Daisuke、Schol Jordy、Sato Masato、Watanabe Masahiko
    • Journal Title

      JOR SPINE

      Volume: 2 Issue: 2

    • DOI

      10.1002/jsp2.1050

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fluorescence-Activated Cell Sorting Is More Potent to Fish Intervertebral Disk Progenitor Cells Than Magnetic and Beads-Based Methods2019

    • Author(s)
      Frauchiger Daniela A.、Tekari Adel、May Rahel D.、D?afo Emina、Chan Samantha C.W.、Stoyanov Jivko、Bertolo Alessandro、Zhang Xingshuo、Guerrero Julien、Sakai Daisuke、Schol Jordy、Grad Sibylle、Tryfonidou Marianna、Benneker Lorin M.、Gantenbein Benjamin
    • Journal Title

      Tissue Engineering Part C: Methods

      Volume: 25 Issue: 10 Pages: 571-580

    • DOI

      10.1089/ten.tec.2018.0375

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IVD progenitor cells: a new horizon for understanding disc homeostasis and repair2019

    • Author(s)
      Lyu Feng-Juan、Cheung Kenneth M.、Zheng Zhaomin、Wang Hua、Sakai Daisuke、Leung Victor Y.
    • Journal Title

      Nature Reviews Rheumatology

      Volume: 15 Issue: 2 Pages: 102-112

    • DOI

      10.1038/s41584-018-0154-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell therapy for intervertebral disc herniation and degenerative disc disease: clinical trials2019

    • Author(s)
      Jordy Schol、Daisuke Sakai
    • Journal Title

      International Orthopaedics

      Volume: 43 Issue: 4 Pages: 1011-1025

    • DOI

      10.1007/s00264-018-4223-1

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of interleukin-17A in nucleus pulposus cells and its small-molecule inhibitors for intervertebral disc disease.2018

    • Author(s)
      Kaori Suyama, Daisuke Sakai, Noriaki Hirayama, Yoshihiko Nakamura, Erika Matsushita, Hayato Terayama, Ning Qu, Osamu Tanaka, Kou Sakabe, Masahiko Watanabe
    • Journal Title

      Journal of Cellular and Molecular Medicine

      Volume: Nov;22 Issue: 11 Pages: 5539-5551

    • DOI

      10.1111/jcmm.13828

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Implantation of hyaluronic acid hydrogel prevents the pain phenotype in a rat model of intervertebral disc injury2018

    • Author(s)
      Mohd Isa Isma Liza、Abbah Sunny A.、Kilcoyne Michelle、Sakai Daisuke、Dockery Peter、Finn David P.、Pandit Abhay
    • Journal Title

      Science Advances

      Volume: 4 Issue: 4

    • DOI

      10.1126/sciadv.aaq0597

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effect of the CCL5-Releasing Fibrin Gel for Intervertebral Disc Regeneration2018

    • Author(s)
      Zhou Zhiyu、Zeiter Stephan、Schmid Tanja、Sakai Daisuke、Iatridis James C.、Zhou Guangqian、Richards R. Geoff、Alini Mauro、Grad Sibylle、Li Zhen
    • Journal Title

      CARTILAGE

      Volume: - Issue: 2 Pages: 169-180

    • DOI

      10.1177/1947603518764263

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Regenerative technologies to bed side: Evolving the regulatory framework2017

    • Author(s)
      Sakai Daisuke、Schol Jordy、Foldager Casper B.、Sato Masato、Watanabe Masahiko
    • Journal Title

      Journal of Orthopaedic Translation

      Volume: 9 Pages: 1-7

    • DOI

      10.1016/j.jot.2017.02.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Animal models for studying the etiology and treatment of low back pain2017

    • Author(s)
      Shi Changgui、Qiu Sujun、Riester Scott M.、Das Vaskar、Zhu Bingqian、Wallace Atiyayein A.、van Wijnen Andre J.、Mwale Fackson、Iatridis James C.、Sakai Daisuke、Votta-Velis Gina、Yuan Wen、Im Hee-Jeong
    • Journal Title

      Journal of Orthopaedic Research

      Volume: - Issue: 5 Pages: 1305-1312

    • DOI

      10.1002/jor.23741

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Histological and reference system for the analysis of mouse intervertebral disc2017

    • Author(s)
      Tam Vivian、Chan Wilson C.W.、Leung Victor Y.L.、Cheah Kathryn S.E.、Cheung Kenneth M.C.、Sakai Daisuke、McCann Matthew R.、Bedore Jake、S?guin Cheryle A.、Chan Danny
    • Journal Title

      Journal of Orthopaedic Research

      Volume: 36 Issue: 1 Pages: 233-243

    • DOI

      10.1002/jor.23637

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Angiopoietin-1 receptor Tie2 distinguishes multipotent differentiation capability in bovine coccygeal nucleus pulposus cells2016

    • Author(s)
      Tekari A, Chan SCW, Sakai D, Grad S, Gantenbein B
    • Journal Title

      Stem Cell Research and therapy

      Volume: 7 Issue: 1 Pages: 75-75

    • DOI

      10.1186/s13287-016-0337-9

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD146 defines commitment of cultured annulus fibrosus cells to express a contractile phenotype2016

    • Author(s)
      Nakai T, Sakai D, Nakamura Y, Nukaga T, Grad S, Li Z, Alini M, Chan D, Mausda K, Ando K, Watanabe M
    • Journal Title

      Journal of Orthopaedic Research

      Volume: 34 Issue: 8 Pages: 1361-72

    • DOI

      10.1002/jor.23326

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs.2016

    • Author(s)
      Rho Nakamichi, Nakamichi R, Ito Y, Inui M, Onizuka N, Kayama T, Kataoka K, Suzuki H, Mori M, Inagawa M, Ichinose S, Lotz M, Sakai D, Masuda K, Ozaki T, Asahara H.
    • Journal Title

      Nature Communications

      Volume: 7 Issue: 1 Pages: 12503-12503

    • DOI

      10.1038/ncomms12503

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Hunt for Transcriptional Control of Nucleus Pulposus Cells using iPS Cell Technology2020

    • Author(s)
      酒井大輔
    • Organizer
      ORS 2020 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] In Silico創薬による新規低分子IL-17A阻害剤を用いた椎間板変性治療の可能性2019

    • Author(s)
      隅山香織、酒井大輔、平山令明、坂部貢、渡辺雅彦
    • Organizer
      第34回日本整形外科学会基礎学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規低分子IL-17A阻害剤による椎間板変性治療法の可能性を評価する2019

    • Author(s)
      隅山香織、酒井大輔、平山令明、坂部貢、渡辺雅彦
    • Organizer
      第48回日本脊椎脊髄病学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Regenerative medicine for intervertebral disc degeneration: Challenges towards realization2019

    • Author(s)
      酒井大輔
    • Organizer
      第48回日本脊椎脊髄病学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Reprogramming the Future of Cell Based Therapy for Intervertebral Disc Disease2019

    • Author(s)
      酒井大輔
    • Organizer
      ICRS 2019 International Cartilage Repair Society 15th World Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 椎間板再生におけるスフェロイド形成培養法に関する基礎的検討2019

    • Author(s)
      酒井大輔
    • Organizer
      第34回日本整形外科学会基礎学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腰痛診療up date2019~新腰痛診療ガイドラインからiPS細胞技術による椎間板再生まで~2019

    • Author(s)
      酒井大輔
    • Organizer
      第3回日本リハビリテーション医学会秋季学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 表面マーカーを用いた細胞機能解析による椎間板再生の新知見2016

    • Author(s)
      酒井大輔
    • Organizer
      第45回日本脊椎脊髄病学会学術集会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 椎間板再生医療が開く脊椎変性疾患治療の未来2016

    • Author(s)
      酒井大輔
    • Organizer
      第89回日本整形外科学会学術総会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Remarks] 東海大の取り組む椎間板再生医療

    • URL

      http://sekitsui.med.u-tokai.ac.jp

    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] IL-17受容体結合部の阻害によるIL-17活性の制御方法2019

    • Inventor(s)
      酒井大輔、隅山香織、平山令明
    • Industrial Property Rights Holder
      学校法人東海大学、日本臓器製薬株式会社
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-030061
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] Tie2陽性幹/前駆細胞を含む細胞集団の培養方法およびその利用2019

    • Inventor(s)
      酒井大輔、中村嘉彦、松下枝利香
    • Industrial Property Rights Holder
      学校法人東海大学、日本臓器製薬株式会社
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] Tie2陽性幹/前駆細胞を含む細胞集団の培養方法およびその利用2019

    • Inventor(s)
      酒井大輔、中村嘉彦、松下枝利香
    • Industrial Property Rights Holder
      学校法人東海大学、日本臓器製薬株式会社
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-163750
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 髄核細胞マスターレギュレーター転写因子を含む分化誘導剤、誘導髄核細胞の製造方法、および誘導髄核細胞の用途2019

    • Inventor(s)
      酒井大輔、ジルディ ショール、平石駿介、升井伸治
    • Industrial Property Rights Holder
      学校法人東海大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-066535
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] Tie2陽性幹/前駆細胞を含む細胞集団の培養方法およびその利用2019

    • Inventor(s)
      酒井大輔、中村嘉彦、松下枝利香
    • Industrial Property Rights Holder
      学校法人東海大学、日本臓器製薬株式会社
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-546051
    • Filing Date
      2019
    • Acquisition Date
      2020
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 髄核マスターレギュレーター転写因子を含む分化転換剤、誘導髄核細胞の製造方法、および誘導髄核細胞の用途2019

    • Inventor(s)
      酒井大輔、ジョルディショール、平石駿介、升井伸治
    • Industrial Property Rights Holder
      酒井大輔、ジョルディショール、平石駿介、升井伸治
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-066535
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2022-08-19  

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