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A new therapeutic approach to bradyarrhythmias using regenerated myocardium 〜 development of biological pacemaker

Research Project

Project/Area Number 16590676
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionNagoya University

Principal Investigator

LEE Jong-Kook  Nagoya University, Research Institute of Environmental Medicine, Associate Professor, 環境医学研究所, 助教授 (60303608)

Co-Investigator(Kenkyū-buntansha) HIDAKA Kyoko  National Cardiovascular Center Research Institute, Department of Bioscience, バイオサイエンス部, 室長 (00216681)
MORISAKI Takayuki  National Cardiovascular Center Research Institute, Department of Bioscience, バイオサイエンス部, 部長 (30174410)
KODAMA Itsuo  Nagoya University, Research Institute of Environmental Medicine, Professor, 環境医学研究所, 教授 (30124720)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
KeywordsES cell / biological pacemaker / regenerated myocardium / bradyarrhythmias / gap junction / teratomas / 再生医学 / 胚性幹(ES)細胞
Research Abstract

Nkx2.5-GFP knock-in murine ES cells were established by inserting GFP into Nkx2.5 allele. Embryoid bodies obtained with "hanging-drop" method were dispersed on day 10, and GFP-positive cells were isolated as ES cell-derived cardiac myocytes (ESCMs) using a fluorescence activated cell sorter (Hidaka et al. FASEB J 2003). Complete AV block (AVB) was created in mice by injecting PBS containing 10-20% glycerol into the AV nodal region. Five days after the operation, ESCMs (2×10^5) were injected into the AV nodal region. ECGs were continuously monitored with a telemetry system for 10 days. Expression of gap junctions was estimated by immunohistochemistry for connexin43 and 40 (Cx43/Cx40). AVB mice injected with PBS alone were used as references. The mice injected with PBS alone showed complete AVB throughout the entire observation period (HR:168±10 bpm, n=5). In contrast, four out of five mice injected with ESCMs restored AV conduction after the injection (HR:683±50 bpm, n=4). Ectopic pacemaker activity such as accelerated junctional rhythm was not observed in the ESCMs-transplanted mice after the cell transplantation. In the non-transplanted mice injected with PBS alone, marked fibrosis and discontinuity of Cx43/Cx40 expression were observed in the AV nodal region, whereas in the mice injected with ESCMs, substantial amounts of immunolabeled Cx43/Cx40 were recognized between ESCMs and the host cardiac myocytes. Transplantation of ESCMs restored the AV conduction in the mouse heart with surgically created complete AVB. Targeted local injection of ESCMs could be a novel therapeutic approach to treat life-threatening bradyarrhythmias.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (21 results)

All 2005 2004 2003

All Journal Article (21 results)

  • [Journal Article] Subtype Switching of L-Type Ca^2+ Channel From Ca_v 1.3 to Ca_v 1.2 in Embryonic Murine Ventricle2005

    • Author(s)
      Takemura H, Yasui K, Opthof T, Niwa N, Horiba M, Shimizu A, Lee JK, Honjo H, Kamiya K, Ueda Y, Kodama I
    • Journal Title

      Circulation Journal 69

      Pages: 1405-1411

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Decreased Vagal Control over Heart Rate in Rats with Right-Sided Congestive Heart Failure2005

    • Author(s)
      Nihei M, Lee Jk, Honjo H, Yasui K, Uzzaman M, Kamiya K, Opthof T, Kodama I
    • Journal Title

      Circulation Journal 69

      Pages: 493-499

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 「バイオペースメーカ」の創生2005

    • Author(s)
      李 鍾國
    • Journal Title

      ICUとCCU 29

      Pages: 547-552

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] 不整脈における分子機構 : 不整脈病態におけるゲノミクス2005

    • Author(s)
      李 鍾國
    • Journal Title

      最新医学 60

      Pages: 2286-2293

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 不整脈の遺伝子・細胞治療2005

    • Author(s)
      李 鍾國
    • Journal Title

      Current Therapy 23

      Pages: 21-26

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Subtype Switching of L-Type Ca^<2+> Channel From Ca_v1.3 to Ca_v1.2 in Embryonic Murine Ventricle2005

    • Author(s)
      Takemura H, Yasui K, Opthof T, Niwa N, Horiba M, Shimizu A, Lee JK, Honjo H, Kamiya K, Ueda Y, Kodama I.
    • Journal Title

      Circulation Journal. 69

      Pages: 1405-1411

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Decreased Vagal Control over Heart Rate in Rats with Right-Sided Congestive Heart Failure2005

    • Author(s)
      Nihei M, Lee JK, Honjo H, Yasui K, Uzzaman M, Kamiya K, Opthof T, Kodama I.
    • Journal Title

      Circulation Journal. 69

      Pages: 493-499

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Creation of biological pacemaker2005

    • Author(s)
      Lee J.
    • Journal Title

      Japanese Journal of Intensive Care Medicine. 29

      Pages: 547-552

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Molecular basis for arrhythmias : Genomics of pathophysiology of arrhythmogenicity2005

    • Author(s)
      Lee J.
    • Journal Title

      The Medical Frontline. 60

      Pages: 2286-2293

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene therapy and cell based therapy for arrhythmias2005

    • Author(s)
      Lee J.
    • Journal Title

      Current Therapy. 23

      Pages: 21-26

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Subtype Switching of L-Type Ca^<2+> Channel From Ca_v1.3 to Ca_v1.2 in Embryonic Murine Ventricle2005

    • Author(s)
      Haruki Takemura
    • Journal Title

      Circulation Journal 69

      Pages: 1405-1411

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Decreased Vagal Control over Heart Rate in Rats with Right-Sided Congestive Heart Failure2005

    • Author(s)
      Motoki Nihei
    • Journal Title

      Circulation Journal 69

      Pages: 493-499

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Combined effects of nifekalant and lidocaine on the spiral-type re-entry in a perfused 2-dimensional layer of rabbit ventricular myocardium2005

    • Author(s)
      Mari Amino
    • Journal Title

      Circulation Journal 69

      Pages: 576-584

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 不整脈における分子機構:不整脈病態におけるゲノミクス2005

    • Author(s)
      李 鍾國
    • Journal Title

      最新医学 60

      Pages: 2286-2293

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Decreased Vagal Control over Heart Rate in Rats with Right-Sided Congestive Heart Failure.2005

    • Author(s)
      Nihei M, Lee JK, Honjo H, Yasui K, Uzzaman M, Kamiya K, Opthof T, Kodama I.
    • Journal Title

      Circ J 69(4)

      Pages: 493-499

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 再生心筋の電気生理2004

    • Author(s)
      李 鍾國
    • Journal Title

      分子心血管病 5(3)

      Pages: 58-63

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Electrophysiology of regenerated myocardium2004

    • Author(s)
      Lee J.
    • Journal Title

      Molecular Cardiovascular Medicine. 5

      Pages: 58-63

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Developmental changes of Ni(2+) sensitivity and automaticity in Nkx2.5-positive cardiac precursor cells from murine embryonic stem cell.2004

    • Author(s)
      Manabe K, Miake J, Sasaki N, Furuichi H, Yano S, Mizuta E, Yamamoto Y, Hoshikawa Y, Yamazaki H, Tajima F, Shiota G, Nanba E, Ohgi S, Hidaka K, Morisaki T, Kurata Y, Lee JK, Igawa O, Shigemasa C, Hisatome I.
    • Journal Title

      Circ J 68(7)

      Pages: 724-726

    • NAID

      110002692186

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mechanosensitivity of GIRK Channels Is Mediated By PKC-dependent Channel-PIP_2 Interaction.2004

    • Author(s)
      Zhang L, Lee JK, John SA, Uozumi N, Kodama I.
    • Journal Title

      L Biol Chem. 279(8)

      Pages: 7037-7047

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Chamber-specific Differentiation of Nkx2.5-positive Cardiac Precursor Cells from Murine Embryonic Stem Cells.2003

    • Author(s)
      Hidaka K, Lee JK, Kim HS, Ihm CH, Iio A, Ogawa M, Nishikawa S, Kodama I, Morisaki T
    • Journal Title

      FASEB J 17(6)

      Pages: 740-742

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Overexpression of calpastatin by gene transfer prevents troponin I degradation and ameliorates contractile dysfunction in rat hearts subjected to ischemia/reperfusion.2003

    • Author(s)
      Maekawa A, Lee JK, Nagaya T, Kamiya K, Yasui K, Horiba M, Miwa K, Uzzaman M, Maki M, Ueda Y, Kodama I.
    • Journal Title

      J Mol Cell Cardiol. 35(10)

      Pages: 1277-1284

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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