Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells

• Project/Area Number: 19K16927
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Keio University
• Principal Investigator: IMAIZUMI Kent 慶應義塾大学, 医学部(信濃町), 特任助教 (10835846)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 領域特異性 / iPS細胞 / 神経幹細胞 / 脊髄損傷 / 再生医療

Outline of Research at the Start

iPS細胞由来神経幹細胞を用いた細胞移植治療は、脊髄損傷に対する有効な治療法として期待される。しかしながら、従来の研究で用いられてきた神経幹細胞は、その脳領域特異性について十分に検討されていない。申請者はこれまでの研究で、iPS細胞由来神経幹細胞を前脳から脊髄までの任意の脳領域に作り分ける技術を開発してきた。本計画では、この技術を用いて、iPS細胞から様々な領域情報を持つ神経幹細胞を作出し、脊髄損傷に対する運動機能改善を検討する。同時に、領域情報による治療効果の差異を通して、神経幹細胞移植による脊髄損傷の治療メカニズムを明らかにする。

Outline of Final Research Achievements

The transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) has beneficial effects on spinal cord injury; however, it remains unknown what subtypes of NPCs are most effective. In this study, we generated region-specific NPC subtypes from human iPSCs and grafted them onto the injured spinal cord in mice. We demonstrated that NPCs with spinal cord identity but not those with forebrain identity resulted in functional improvement in SCI mice.

Academic Significance and Societal Importance of the Research Achievements

脊髄損傷治療における神経幹細胞の領域特異性に着目し、脊髄型神経幹細胞が最も高い治療効果を発揮することを明らかにした。この結果から、iPS細胞を用いた脊髄損傷再生医療において、従来の手法よりも治療効果の優れた神経幹細胞を作成できる可能性を見出すことができた。

Research Products

• [Journal Article] Generation of region-specific and high-purity neurons from human feeder-free iPSCs (2021)
  • Author(s): Sato Tsukika、Imaizumi Kent、Watanabe Hirotaka、Ishikawa Mitsuru、Okano Hideyuki
  • Journal Title: Neuroscience Letters Volume: 746 Pages: 135676-135676
  • DOI: 10.1016/j.neulet.2021.135676
  • Peer Reviewed / Open Access
• [Journal Article] Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons (2021)
  • Author(s): Watanabe Hirotaka、Imaizumi Kent、Cai Tetsuo、Zhou Zhi、Tomita Taisuke、Okano Hideyuki
  • Journal Title: eneuro Volume: 8 Issue: 2 Pages: 0-1
  • DOI: 10.1523/eneuro.0500-20.2021
  • Peer Reviewed / Open Access
• [Journal Article] Non-viral Induction of Transgene-free iPSCs from Somatic Fibroblasts of Multiple Mammalian Species. (2021)
  • Author(s): Yoshimatsu S, Nakajima M, Iguchi A, Sanosaka T, Sato T, Nakamura M, Nakajima R, Arai E, Ishikawa M, Imaizumi K, Watanabe H, Okahara J, Noce T, Takeda Y, Sasaki E, Behr R, Edamura K, Shiozawa S, Okano H.
  • Journal Title: Stem Cell Reports Volume: 16 Issue: 4 Pages: 754-770
  • DOI: 10.1016/j.stemcr.2021.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells (2020)
  • Author(s): Kajikawa Keita、Imaizumi Kent、Shinozaki Munehisa、Shibata Shinsuke、Shindo Tomoko、Kitagawa Takahiro、Shibata Reo、Kamata Yasuhiro、Kojima Kota、Nagoshi Narihito、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s13041-020-00662-w
  • Peer Reviewed / Open Access
• [Journal Article] Human Astrocytes Model Derived from Induced Pluripotent Stem Cells (2020)
  • Author(s): Leventoux Nicolas、Morimoto Satoru、Imaizumi Kent、Sato Yuta、Takahashi Shinichi、Mashima Kyoko、Ishikawa Mitsuru、Sonn Iki、Kondo Takahiro、Watanabe Hirotaka、Okano Hideyuki
  • Journal Title: Cells Volume: 9 Issue: 12 Pages: 2680-2680
  • DOI: 10.3390/cells9122680
  • Peer Reviewed / Open Access
• [Journal Article] Modeling neurodevelopment in a dish with pluripotent stem cells (2020)
  • Author(s): Imaizumi Kent、Okano Hideyuki
  • Journal Title: Development, Growth & Differentiation Volume: 63 Issue: 1 Pages: 18-25
  • DOI: 10.1111/dgd.12699
  • Peer Reviewed / Open Access
• [Journal Article] Single‐cell study of neural stem cells derived from human iPSCs reveals distinct progenitor populations with neurogenic and gliogenic potential (2019)
  • Author(s): Lam Matti、Sanosaka Tsukasa、Lundin Anders、Imaizumi Kent、Etal Damla、Karlsson Fredrik H.、Clausen Maryam、Cairns Jonathan、Hicks Ryan、Kohyama Jun、Kele Malin、Okano Hideyuki、Falk Anna
  • Journal Title: Genes to Cells Volume: 24 Issue: 12 Pages: 836-847
  • DOI: 10.1111/gtc.12731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A combinational treatment of carotenoids decreases Aβ secretion in human neurons via β-secretase inhibition (2019)
  • Author(s): Sho Misato、Ichiyanagi Naoki、Imaizumi Kent、Ishikawa Mitsuru、Morimoto Satoru、Watanabe Hirotaka、Okano Hideyuki
  • Journal Title: Neuroscience Research Volume: － Pages: 47-55
  • DOI: 10.1016/j.neures.2019.10.006
  • Peer Reviewed
• [Presentation] Neural spheroid model for the study of neural patterning (2021)
  • Author(s): Imaizumi Kent, Hideyuki Okano
  • Organizer: The 2nd Stanford-Keio Webinar
• [Presentation] 脊髄損傷治療におけるiPS細胞由来神経細胞の領域特異性の重要性 (2020)
  • Author(s): 梶川慶太、名越慈人、今泉研人、篠崎宗久、神山淳、松本守雄、岡野栄之、中村雅也
  • Organizer: 第19回日本再生医療学会
• [Presentation] Rostrocaudal areal patterning of human ESC/iPSC-derived cortical neurons by FGF8 signaling (2019)
  • Author(s): Imaizumi Kent, Hideyuki Okano
  • Organizer: 第42回日本神経科学大会
• [Presentation] The cerebral cortex patterning in hPSC-derived organoids (2019)
  • Author(s): Imaizumi Kent, Hideyuki Okano
  • Organizer: 20th TMIMS International Symposium
  • Int'l Joint Research
• [Presentation] Recapitulation of the areal patterning in the cerebral cortex by human ESC/iPSC-derived cortical neurons (2019)
  • Author(s): Imaizumi Kent, Hideyuki Okano
  • Organizer: 49th Annual Meeting of the Society for Neuroscience
  • Int'l Joint Research