Molecular mechanisms of the restoration of human APP transgenic mouse cognitive dysfunction after transplant of human iPS cell-derived neural cells

• Project/Area Number: 26501005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Regenerative medicine
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Arimitsu Nagisa 聖マリアンナ医科大学, 医学部, 助教 (40408688)
• Co-Investigator(Kenkyū-buntansha): 藤原 成芳 聖マリアンナ医科大学, 医学部, 助教 (50365425)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 再生医療 / 移植 / 認知症 / 遺伝子発現 / iPS / 記憶 / ヒトiPS細胞

Outline of Final Research Achievements

We examined the molecular mechanisms involved in the alleviation of cognitive dysfunction in transplanted Alzheimer's disease model mice . Neural cells derived from hiPS cells were transplanted to the hilus of the dentate gyrus. After transplant, mice showed improvement in cognitive function. Human choline acetyltransferase (ChAT)-positive cholinergic neurons and small number of vesicular GABA transporter (VGAT)-positive neurons were distributed throughout the cortex of the grafted mice. Human and mouse ChAT and GABA-positive neurons and their receptors of both human origin and mouse origin were significantly increased in the cortex and hippocampus.
The receptor-positive neurons expressed phosphorylated Akt and c-fos in the cortex. And we also confirmed that paracrine factors such as Reelin expressed in the injected area. These suggest that the grafted and host neurons may form positive feedback loops via neurotransmitter secretion in both the cerebral cortex and hippocampus.

Research Products

• [Journal Article] Human iPS cell derived neural cell sheets exhibit mature neural and extendable scaffold functions and promote recovery in injured mouse spinal cords. (2016)
  • Author(s): Arimitsu N, Shimizu J, Iinuma M, Umehara T, Fujiwara N, Takai K, Wakisaka S, Hirotsu C, Suzuki T, Beppu M, Niki H, Suzuki N.
  • Journal Title: J Stem Cell Res Med. Volume: 1 Issue: 2 Pages: 41-47
  • DOI: 10.15761/jscrm.1000106
  • Open Access
• [Journal Article] Cellular and molecular mechanisms of the restoration of human APP transgenic mouse cognitive dysfunction after transplant of human iPS cell-derived neural cells. (2015)
  • Author(s): ・Naruyoshi Fujiwara, Jun Shimizu, Kenji Takai, Nagisa Arimitsu, Yuji Ueda, Sueshige Wakisaka, Tomoko Suzuki, Noboru Suzuki.
  • Journal Title: Experimental Neurology Volume: 271 Pages: 423-431
  • DOI: 10.1016/j.expneurol.2015.07.008
  • Peer Reviewed
• [Presentation] ヒトiPS由来神経細胞移植による認知機能改善と改善メカニズムについての検討 (2017)
  • 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: 第１６回日本再生医療学会総会
  • Place of Presentation: 宮城県仙台市(仙台国際センター)
  • Year and Date: 2017-03-09
• [Presentation] 幹細胞由来神経細胞移植による脳損傷マウスにおける神経再生. (2017)
  • Author(s): 有光なぎさ, 廣津千恵子, 高井憲治, 藤原成芳, 岡田容子、 清水潤, 鈴木登.
  • Organizer: 第１６回日本再生医療学会総会
  • Place of Presentation: 宮城県仙台市(仙台国際センター)
  • Year and Date: 2017-03-07
• [Presentation] 脳損傷マウスに対する幹細胞由来神経細胞移植による神経再生. (2016)
  • Author(s): 有光なぎさ, 廣津千恵子, 高井憲治, 藤原成芳, 清水潤, 鈴木登.
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市(パシフィコ横浜)
  • Year and Date: 2016-12-02
• [Presentation] RESTORATION OF HUMAN APP TRANSGENIC MOUSE COGNITIVE DYSFUNCTION AFTER TRANSPLANT OF HUMAN IPS CELL-DERIVED NEURAL STEM/PRECURSOR CELLS. (2016)
  • Author(s): Fujiwara Naruyoshi, Kenji Takai, Chieko Hirotsu, Erika Takada, Nagisa Arimitsu, Jun Shimizu and Noboru Suzuki.
  • Organizer: International society for stem cell research 12th annual meeting
  • Place of Presentation: CALIFORNIA USA
  • Year and Date: 2016-06-22
  • Int'l Joint Research