Establishment of differentiation induction method from iPS cells to mature oligodendrocytes and application to myelin sheath regeneration therapy

• Project/Area Number: 17K07120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Defense Medical College
• Principal Investigator: IMAMURA OSAMU 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 生化学, 准教授 (40534954)
• Co-Investigator(Kenkyū-buntansha): 瀧嶋 邦夫 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 生化学, 教授 (50531365)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脱髄疾患 / ドネペジル / エストロゲン受容体 / iPS細胞 / オリゴデンドロサイト / 神経幹細胞 / 髄鞘形成

Outline of Final Research Achievements

In this study, we elucidated the mechanism of action of donepezil (DNP) induction of oligodendrocyte differentiation using iPS cells, and developed a DNP-based oligodendrocyte differentiation induction method to be used for demyelination therapy. The results of this study revealed that the estrogen receptor (ER)-mediated pathway is important for DNP-induced differentiation of mouse iPS cell-derived neural stem cells into oligodendrocytes. In addition, we confirmed that DNP also induces differentiation of human iPS cells into oligodendrocytes.

Academic Significance and Societal Importance of the Research Achievements

脱髄疾患の治療標的は免疫系であり、疾患の進行抑制と再発予防を狙った対症療法が主体となっている。本研究においてDNPによるオリゴデンドロサイトへの分化促進作用にはERを介する経路が重要であることを明らかにした。ER経路の活性化は、オリゴデンドロサイトへの分化誘導や髄鞘形成を促進させ、脱髄疾患モデル動物の病態を改善することが報告されているため、今後、本研究成果に基づきオリゴデンドロサイト分化誘導活性を標的にした新たな脱髄疾患治療薬の創出が期待される。

Research Products

• [Journal Article] Donepezil-induced Oligodendrocyte Differentiation Is Mediated Through Estrogen Receptors (2020)
  • Author(s): Osamu Imamura , Masaaki Arai , Minori Dateki , Kazuhiko Oishi , Kunio Takishima
  • Journal Title: J Neurochem Volume: 155（5） Issue: 5 Pages: 494-507
  • DOI: 10.1111/jnc.14927
  • Peer Reviewed
• [Journal Article] Donepezil promotes differentiation of neural stem cells into mature oligodendrocytes at the expense of astrogenesis. (2017)
  • Author(s): Imamura O, Arai M, Dateki M, Takishima K.
  • Journal Title: J Neurochem. Volume: 140 Pages: 231-244
  • Peer Reviewed
• [Presentation] Donepezil promotes differentiation of neural stem cells into mature oligodendrocytes at the expense of astrogenesis (2017)
  • Author(s): Imamura O, Arai M, Dateki M, Takishima K.
  • Organizer: 第40回日本神経科学大会