Transplantation of Human iPS cell derived neurons to Dementia model mice

• Project/Area Number: 17K01378
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomedical engineering/Biomaterial science and engineering
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Fujiwara Naruyoshi 聖マリアンナ医科大学, 医学部, 講師 (50365425)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 認知症 / 神経幹細胞 / reelin / シナプス / Disabled1 / EphrinB / コリン作動性神経 / 内側中隔核 / ブローカの対角帯垂直部 / 神経再生 / 神経移植 / ヒトiPS細胞 / 認知機能 / 再生医学 / 脳神経疾患 / 移植 / 神経科学

Outline of Final Research Achievements

In the hippocampus of dementia model mice, Reelin and phosphorylated Dab1 decreased, and as a result, EphrinB/EphB is decreased. We found that neural stem cells transplanted to the hippocampus of dementia mice produce Reelin and phosphorylate Dab1 and Akt downstream thereof, further activate synapse formation and reconstruct neural circuits downstream. Neural stem cell transplantation, together with Reelin, is likely to result in increased production of Ephrin B and synapse formation. Specifically, in the presence of Reelin stimulation, Ephrin B3 forms a complex with ApoER2 to develop synapses in normal mice, and there is the abnormality in the hippocampus of dementia mice, which may lead to synaptic hypoplasia.

Academic Significance and Societal Importance of the Research Achievements

国内外の多くの研究者は認知症モデル動物を用いて神経細胞移植での根治療法を探っている。ヒトへの臨床応用については免疫拒絶反応の問題が発生し、さらに倫理的な観点からの問題も研究遂行の障壁となる点が存在する。ヒトへの応用を第一に考え、我々は本研究においてhiPS細胞を用いることを提案している。
本研究は認知機能の改善に神経幹細胞移植の効果を認知症マウスで試みる研究として世界的に先頭を走ると考えている。認知症の根治療法の開発は認知症患者のみならず、介護にあたる家族にとっても悲願である。本研究は認知症による経済的損失解決のためにも全世界に貢献できるものと考えている。

Research Products

• [Journal Article] Relative abundance of Megamonas hypermegale and Butyrivibrio species decreased in the intestine and its possible association with the T cell aberration by metabolite alteration in patients with Behcet's disease. (2019)
  • Author(s): Shimizu J, Kubota T, Suzuki N et al.
  • Journal Title: Clinical Rheumatology Volume: 9 Issue: 5 Pages: 1-9
  • DOI: 10.1007/s10067-018-04419-8
  • Peer Reviewed / Open Access
• [Journal Article] Roles of Reelin/Disabled1 pathway on functional recovery of hemiplegic mice after neural cell transplantation; Reelin promotes migration toward motor cortex and maturation to motoneurons of neural grafts. (2019)
  • Author(s): Arimitsu N, Takai K, Fujiwara N, Shimizu J, Ueda Y, Wakisaka S, Hirotsu C, Murayama M A, Suzuki T, Suzuki N
  • Journal Title: Exp Neurol Volume: 320 Pages: 112970-112970
  • DOI: 10.1016/j.expneurol.2019.112970
  • Peer Reviewed / Open Access
• [Journal Article] Cellular and Molecular Mechanisms Governing Functional Recovery of Dementia Mice after Neuronal cell Transplantation. (2018)
  • Author(s): Suzuki N, Shimizu J, Takai K, Arimitsu N, Suzuki T, Fujiwara N.
  • Journal Title: Journal of Neuroscience and Neurosurgery Volume: 1 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Propionate-producing bacteria in the intestine may associate with skewed responses of IL10-producing regulatory T cells in patients with relapsing polychondritis. (2018)
  • Author(s): Shimizu J, Kubota T, Takada E, Takai K, Fujiwara N, Arimitsu N, Murayama MA, Ueda Y, Wakisaka S, Suzuki T, Suzuki N
  • Journal Title: PLoS One Volume: 20 Issue: 9 Pages: e0203657-e0203657
  • DOI: 10.1371/journal.pone.0203657
  • Peer Reviewed / Open Access
• [Journal Article] Cellular and Molecular Mechanisms Governing Functional Recovery of Dementia Mice after Neuronal cell Transplantation. (2018)
  • Author(s): Suzuki N, Shimizu J, Takai K, Arimitsu N, Suzuki T, Fujiwara N.
  • Journal Title: Journal of Neuroscience and Neurosurgery. Volume: 1(2) Pages: 1-8
  • Peer Reviewed
• [Journal Article] Neuronal cell sheets of cortical motor neuron phenotype derived from human iPS cells. (2017)
  • Author(s): Suzuki N, Arimitsu N, Shimizu J, Takai K, Hirotsu C, Ueda Y, Wakisaka S, Fujiwara N, Suzuki T.
  • Journal Title: Cell Transplant. Volume: 26 Issue: 8 Pages: 1355-1364
  • DOI: 10.1177/0963689717720280
  • Peer Reviewed / Open Access
• [Presentation] ヒトiPS由来神経細胞移植による認知機能改善メカニズムについての検討 (2019)
  • Author(s): 藤原成芳, 高井憲治, 清水潤，鈴木登.
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] 認知症モデルマウスを用いたヒトiPS由来神経細胞移植による認知機能改善における心理症状の評価と関連 (2019)
  • Author(s): 村山正承, 藤原成芳, 高井憲治, 清水潤, 鈴木登
  • Organizer: 第66回日本実験動物学会総会
• [Presentation] 神経移植による認知機能回復における神経再生及び回復メカニズムの解明 (2019)
  • Author(s): 藤原 成芳, 村山 正承, 岡田 容子, 高井 憲治, 廣津 千恵子, 高田 えりか, 有光 なぎさ, 清水 潤, 鈴木 登
  • Organizer: 日本再生医療学会
• [Presentation] A STUDY ON THE IMPORTANCE OF REGENERATION OF GABAERGIC NEURONS IN RESTORING COGNITIVE FUNCTION BY HIPS DERIVED NEURAL CELL TRANSPLANTATION TO DEMENTIA MODEL MICE. (2018)
  • Author(s): Fujiwara Naruyoshi, Takai Kenji, Shimizu Jun and Suzuki Noboru
  • Organizer: International society for stem cell research 14th annual meeting
  • Int'l Joint Research
• [Presentation] ヒトiPS由来神経細胞移植による認知機能改善における改善メカニズムの解明 (2018)
  • Author(s): 藤原成芳、岡田容子、 高井憲治、廣津千恵子、有光なぎさ、 高田えりか、清水潤、鈴木登
  • Organizer: 日本再生医療学会総会
• [Presentation] RESTORATION OF REELIN/APOER2 INTERACTION RESTORE COGNITIVE DYSFUNCTION OF DEMENTIA MODER MICE AFTER TRANSPLANTATIOB OF HUMAN IPS CELL-DERIVED NEURAL STEM/PRECURSOR CELLS. (2017)
  • Author(s): Fujiwara Naruyoshi, Takai Kenji, Shimizu Jun and Suzuki Noboru.
  • Organizer: International society for stem cell research 13th annual meeting
  • Int'l Joint Research