The development of novel therapies for intractable epilepsy with bone marrow mesenchymal stem cells

• Project/Area Number: 16K09993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Sapporo Medical University
• Principal Investigator: Fukumura Shinobu 札幌医科大学, 医学部, 助教 (30718341)
• Co-Investigator(Kenkyū-buntansha): 佐々木 祐典 札幌医科大学, 医学部, 講師 (20538136) ; 本望 修 札幌医科大学, 医学部, 教授 (90285007) ; 坂井 拓朗 札幌医科大学, 医学部, 研究員 (80639229)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: てんかん / 再生医療 / 幹細胞 / 骨髄間葉系幹細胞 / 細胞治療 / 神経再生

Outline of Final Research Achievements

The present study tested the hypothesis that systemically infused mesenchymal stem cells (MSCs) reduce epileptogenesis by inhibiting neuronal cell death and suppressing aberrant MFS, leading to preservation of cognitive function in a rat model of epilepsy. Status epilepticus (SE) was induced using the lithium-pilocarpine injection. MSC infusion inhibited epileptogenesis and preserved cognitive function after SE. The infused MSCs preserved GAD67+ and NeuN+ hippocampal neurons. Furthermore, the MSC infusion suppressed the aberrant MFS in the hippocampus as evidenced by manganese enhanced MRI and Timm staining. This study demonstrated that the intravenous infusion of MSCs mitigated epileptogenesis, thus advancing MSCs as an effective approach for epilepsy in clinical practice.

Academic Significance and Societal Importance of the Research Achievements

従来の抗てんかん薬は、けいれん発作は抑えるが、形成された異常神経回路（てんかん回路）を正常化する治療法ではないため、治療の長期化や認知機能への影響が問題となっており、より根本的で有効な治療法が望まれている。本研究において、けいれん重積後の急性期に骨髄間葉系幹細胞を移植により、てんかん発症予防効果および認知機能低下予防効果を示した。さらにてんかん回路を正常化するメカニズムとして、骨髄間葉系幹細胞による海馬細胞消失の軽減、異常神経回路形成の抑制が起こることを明らかにし、新たな創薬ターゲットにもつながる知見が得られた。

Research Products

• [Journal Article] Intravenous infusion of mesenchymal stem cells reduces epileptogenesis in a rat model of status epilepticus. (2018)
  • Author(s): Fukumura, S., Sasaki, M., Kataoka-Sasaki, Y., Oka, S., Nakazaki, M., Nagahama, H., Morita, T., Sakai, T., Tsutsumi, H., Kocsis, J.D., Honmou, O.
  • Journal Title: Epilepsy Reserch Volume: 141 Pages: 56-63
  • DOI: 10.1016/j.eplepsyres.2018.02.008
  • Peer Reviewed
• [Presentation] Intravenous infusion of mesenchymal stem cells reduces epileptogenesis in a rat model of status epilepticus. (2018)
  • Author(s): Fukumura S（Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan）, Sasaki M, Honmou O（Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan）
  • Organizer: American Epilepsy Society Annual meeting 2018（2018.11.30-12.5 New Orleans, USA）
  • Int'l Joint Research