Modeling Duchenne muscular dystrophy using patient-derived iPS cells

• Project/Area Number: 24790383
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Kyoto University
• Principal Investigator: SAKURAI Hidetoshi 京都大学, iPS細胞研究所, 講師 (80528745)
• Co-Investigator(Renkei-kenkyūsha): MATSUO Masafumi 神戸学院大学, 大学院総合リハビリテーション学部, 教授 (10157266) ; AWAYA Tomonari 京都大学, 大学院医学研究科発達小児科学, 助教 (20589593)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: iPS細胞 / 疾患再現 / 筋ジストロフィー / デュシェンヌ型筋ジストロフィー / 細胞内カルシウムイメージング / 疾患特異的iPS細胞 / 病態再現 / 骨格筋細胞 / 創薬スクリーニング

Research Abstract

In this study, we demonstrated the early pathogenesis of Duchenne muscular dystrophy (DMD) using patient-derived iPS cells. DMD-muscles differentiated from DMD-iPSCs exhibited similar gene expression profile and similar maturity as control iPSC-derived muscles, and no differentiation delay was observed in DMD-muscles. When DMD-muscles were exposed to electric stimulation, higher intracellular Ca2+ influx was observed in DMD-muscles than control-muscles. Larger cell damage was observed in DMD-muscles than control-muscles through overloading Ca2+ by ionomycin. Since these phenotype could be ameliorated by restored dystrophin expression by exon skip technics, we conclude that excessive Ca2+ influx is the trigger for the early pathogenesis of DMD caused by absence of dystrophin. According to our findings, we are going to develop new drugs targeting excessive Ca2+ influx by analyzing the mechanism which is caused by absence of dystrophin.

Research Products

• [Journal Article] Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Myoshi Myopathy in vitro (2013)
  • Author(s): 田中章仁, Knut Woltjen, 三宅克也,堀田秋津,池谷真,山本拓也,西野永希子,庄子栄美i,瀬原淳子,真鍋康子,藤井宣晴,花岡和則,江良拓実,山下賢,磯部健一,木村円,櫻井英俊
  • Journal Title: PLOS ONE Volume: 4
  • Peer Reviewed
• [Presentation] 疾患特異的iPS細胞を活用した筋疾患研究 (2014)
  • Author(s): 櫻井英俊
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2014-03-05
  • Invited
• [Presentation] Modeling Duchenne muscular dystrophy by patient-derived iPS cells (2014)
  • Author(s): Emi Shoji, Sakurai Hidetoshi
  • Organizer: The 7^<th> Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 大阪市
• [Presentation] Modeling Duchenne muscular dystrophy by patient-derived iPS cells (2014)
  • Author(s): Emi Shoji, Hidetoshi Sakurai
  • Organizer: The 7th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 大阪市
• [Presentation] 転写因子を用いた効率的なヒトiPS細胞からの骨格筋細胞誘導法の確立と細胞療法、疾患モデルへの応用 (2013)
  • Author(s): 田中章仁、櫻井英俊
  • Organizer: 第12回 日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Modelling Duchenne muscular dystrophy (DMD) with human induced pluripotent stem cells (2012)
  • Author(s): Emi Shoji, Hidetoshi Sakurai
  • Organizer: 第7回研究所ネットワーク国際シンポジウム
  • Place of Presentation: 東北大学
• [Presentation] デュシェンヌ型筋ジストロフィー患者由来iPS細胞を用いての病態再現 (2012)
  • Author(s): 庄子栄美、櫻井英俊
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡マリンメッセ