Comprehensive development of next-generation direct reprogramming method applicable to treatment for various neurological diseases

• Project/Area Number: 17K10827
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Okayama University
• Principal Investigator: Yamashita Toru 岡山大学, 医歯薬学総合研究科, 講師 (60644408)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脳梗塞 / iN細胞 / ダイレクトリプログラミング

Outline of Final Research Achievements

In this study, we conducted experiments to express Ascl1, Sox2, and NeuroD1 in glial cells in the post-stroke brain of mice using retrovirus. As a result, it was revealed that neural progenitor cells were induced 24 days after the retrovirus injection and mature neurons were induced 52 days. These results suggested that nerve cells can be reproduced from the abundant remaining glial cells in the brain. In the future, we will further improve the induction efficiency, establish safety and promote the development of treatment methods that contribute to the improvement of motor paralysis in patients with ischemic stroke.

Academic Significance and Societal Importance of the Research Achievements

今回、神経特異的転写因子であるAscl1やSox2、NeuroD1を脳内グリア細胞に強制発現させることで、神経系細胞に直接的に誘導することができ、脳梗塞で一旦失われてしまった神経細胞も、周囲に豊富に残っているグリア細胞から誘導し補充できる可能性が示すことが出来た。今後3つの転写因子を発現できる高力価ポリシストロニックベクター等を用いるなど、誘導効率を更に向上させると共に安全性を確立し、脳梗塞患者の運動麻痺改善に寄与する治療法開発を進めていく。

Research Products

• [Journal Article] In vivo direct reprogramming of glial linage to mature neurons after cerebral ischemia (2019)
  • Author(s): Yamashita Toru、Shang Jingwei、Nakano Yumiko、Morihara Ryuta、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Ohta Yasuyuki、Abe Koji
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10956-10956
  • DOI: 10.1038/s41598-019-47482-0
  • Peer Reviewed / Open Access
• [Journal Article] Novel Therapeutic Transplantation of Induced Neural Stem Cells for Stroke. (2017)
  • Author(s): Yamashita T, Liu W, Matsumura Y, Miyagi R, Zhai Y, Kusaki M, Hishikawa N, Ohta Y, Kim SM, Kwak TH, Han DW, Abe K.
  • Journal Title: Cell Transplant. Volume: Mar 13;26(3) Issue: 3 Pages: 461-467
  • DOI: 10.3727/096368916x692988
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] In vivo direct reprogramming of glial linage to mature neurons after cerebral ischemia. (2019)
  • Author(s): Yamashita Toru、Shang Jingwei、Nakano Yumiko、Morihara Ryuta、Sato Kota、Takemoto Mami、Hishikawa Nozomi、Ohta Yasuyuki、Abe Koji
  • Organizer: Asia Pacific Stroke Conference 2019
  • Int'l Joint Research
• [Presentation] 虚血脳内グリア細胞から神経細胞を誘導するダイレクトリプログラミング法の確立 (2019)
  • Author(s): 山下徹、商敬偉、中野由美子、森原隆太、佐藤恒太、武本麻美、菱川望、 太田康之、阿部康二
  • Organizer: 第62回日本脳循環代謝学会学術集会
  • Invited
• [Presentation] 脳内グリア細胞からの神経再生実現にむけて (2017)
  • Author(s): 山下徹、阿部康二
  • Organizer: 第1回先進医薬研究報告会
• [Book] メディカルサイエンスダイジェスト ~多様な神経疾患治療に応用可能な次世代型ダイレクトリプログラミング法の開発 (2018)
  • Author(s): 山下徹、阿部康二
  • Total Pages: 44
  • Publisher: ニュー・サイエンス社
• [Book] Cell Therapy Against Cerebral Stroke (iPS Cells and iN Cells) (2017)
  • Author(s): Houkin, Kiyohiro, Abe, Koji, Kuroda, Satoshi
  • Total Pages: 156
  • Publisher: Springer
  • ISBN: 9784431560593
• [Remarks] 脳梗塞後に神経細胞を新たに生み出すことに成功！ ～脳内グリア細胞から神経細胞を誘導する新技術を開発～
  • URL: https://www.okayama-u.ac.jp/up_load_files/press2019/press20190927-2.pdf
• [Remarks] Rising from the ashes
  • URL: https://www.okayama-u.ac.jp/eng/research_highlights/index_id93.html