Visualization of spatiotemporal dynamics of iPS cell-derived neural stem cells migration and glioma stem cell invasion

• Project/Area Number: 18K16570
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Keio University
• Principal Investigator: OISHI Yumiko 慶應義塾大学, 医学部(信濃町), 助教 (50793121)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 悪性神経膠腫 / iPS細胞 / 神経幹細胞 / 遊走 / 脳切片培養 / スライスカルチャー / 自殺遺伝子 / 再生医療 / Brain slice culture / グリオーマ幹細胞 / slice culture / 幹細胞 / iPS

Outline of Final Research Achievements

In this study, we visualized the spatiotemporal dynamics of invasion of glioma stem cells (GSCs) and migration of human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) in an orthotopic xenograft mouse model using time-lapse imaging of organotypic brain slice cultures. GSCs implanted in the striatum exhibited directional invasion toward axon bundles, perivascular area, and the subventricular zone around the inferior horn of the lateral ventricle. Time-lapse imaging of organotypic brain slice cultures first demonstrated the directional migration of NSCs with suicide gene toward GSCs and the bystander killing effect. The present methodology can efficiently visualize the behavior of implanted cells, leading to the clinical application.

Academic Significance and Societal Importance of the Research Achievements

ヒトiPS細胞から分化誘導したNSCと自殺遺伝子治療を組み合わせたグリオーマに対する新規遺伝子細胞療法の開発を続けてきた。NSCは腫瘍や損傷部位へ遊走することができるため、治療遺伝子の細胞運搬体として使用することができ、脳腫瘍に対する治療のみならず、脳梗塞、脊髄損傷等あらゆる疾患にも応用できる。本研究開発では、可視化技術と脳切片培養法を組み合わせた独自の方法により、生体内での移植細胞の挙動や治療効果をリアルタイムに詳細かつ長期間定量的に解析した。今回樹立したスクリーニング法により、幹細胞を用いた移植細胞療法を臨床応用する上で、その治療効果を効率的に評価可能となる。

Research Products

• [Journal Article] Gene Therapy Using Neural Stem/Progenitor Cells Derived from Human Induced Pluripotent Stem Cells: Visualization of Migration and Bystander Killing Effect. (2020)
  • Author(s): Tamura R, Miyoshi H, Morimoto Y, Oishi Y, Sampetrean O, Iwasawa C, Mine Y, Saya H, Yoshida K, Okano H, Toda M.
  • Journal Title: Hum Gene Ther. Volume: 31(5-6) Issue: 5-6 Pages: 352-366
  • DOI: 10.1089/hum.2019.326
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Visualization of spatiotemporal dynamics of human glioma stem cell invasion (2019)
  • Author(s): Tamura Ryota、Miyoshi Hiroyuki、Sampetrean Oltea、Shinozaki Munehisa、Morimoto Yukina、Iwasawa Chizuru、Fukaya Raita、Mine Yutaka、Masuda Hirotaka、Maruyama Tetsuo、Narita Minoru、Saya Hideyuki、Yoshida Kazunari、Okano Hideyuki、Toda Masahiro
  • Journal Title: Molecular Brain Volume: 12 Issue: 1
  • DOI: 10.1186/s13041-019-0462-3
  • Peer Reviewed / Open Access
• [Presentation] HSV-TK suicide gene therapy for glioblastoma using neural stem/progenitor cells derived from human induced pluripotent stem cells (2019)
  • Author(s): 三好浩之、田村亮太、森本佑紀奈、サンペトラ・オルテア、岩澤千鶴、峯裕、成田年、葛巻直子、佐谷秀行、吉田一成、岡野栄之、戸田正博
  • Organizer: 第25回 日本遺伝子細胞治療学会
• [Presentation] HSV-TK suicide gene therapy for glioblastoma using neural stem/progenitor cells derived from human induced pluripotent stem cells (2019)
  • Author(s): Hiroyuki Miyoshi, Ryota Tamura, Yukina Morimoto, Oltea Sampetrean, Chizuru Iwasawa, Yutaka Mine, Minoru Narita, Hideyuki Saya, Kazunari Yoshida, Hideyuki Okano, Masahiro Toda
  • Organizer: Annual Meeting of JSGCT
• [Patent(Industrial Property Rights)] 脳腫瘍幹細胞を用いた治療薬スクリーニング法 (2018)
  • Inventor(s): 戸田正博、田村亮太、岡野栄之、三好浩之
  • Industrial Property Rights Holder: 戸田正博、田村亮太、岡野栄之、三好浩之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-052704
  • Filing Date: 2018
  • Acquisition Date: 2019