Paracrine control and therapeutic application in recovery of brain damage by stem cell-derived nerve cell transplantation

• Project/Area Number: 17K10852
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経 / 移動 / 幹細胞 / 前駆細胞 / Reelin / 片マヒ / 幹・前駆細胞移植 / 神経再生 / リーリンシグナル経路 / 移植 / 神経細胞 / 脳損傷 / 再生 / 再生医学

Outline of Final Research Achievements

We focused on Reelin, a paracrine factor found in the search for related factors in frozen injured brain model mice. We investigated the transplantation of neural stem/progenitor cells of spontaneously mutated mice of Disabled 1 (Dab1), Yotari, which is an adapter factor of Reelin signaling pathway. As a result of comparison with wild-type cell transplantation and Yotari-derived neural stem/progenitor cells, it was found that some factors downstream of the Reelin pathway are involved in the recovery of motor function.
The localization and cell feature of labeled cells derived of transplanted cell indicates that the Reelin pathway of transplanted cells themselves is involved in cell migration and nerve regeneration in the injured cortex area. We reported these results in an international journal (Arimitsu, 2019).

Academic Significance and Societal Importance of the Research Achievements

本解析は運動皮質の脳表損傷片マヒモデルのため損傷部位への移動、層構造形成が見やすい系であり、用いる移植細胞は幹細胞よりもさらに運動神経細胞に近づけた細胞移植で、より移植部位での環境に近づけ定着しやすくしている点で細胞移植応用につながる意義がある。さらに、これまで発生過程で主に機能すると考えられていたReelinが成体においても損傷時に再活性化して損傷回復過程で機能する点で注目している因子が分泌性因子であることから、移植法だけにとどまらず、外的因子の導入による治療法の検討などを展開できる点に学術的意義、社会的意義があると考えられる。

Research Products

• [Journal Article] Interaction between SDF1 and CXCR4 Promotes Photoreceptor Differentiation via Upregulation of NFκB Pathway Signaling Activity in Pax6 Gene-Transfected Photoreceptor Precursors. (2020)
  • Author(s): Shimizu J, Suzuki T, Hirotsu C, Ueno H, Takada E, Arimitsu N, Ueda Y, Wakisaka S, Suzuki N.
  • Journal Title: Ophthalmic Res. Volume: 14 Issue: 4 Pages: 1-12
  • DOI: 10.1159/000503929
  • Peer Reviewed / Open Access
• [Journal Article] Transplantation of Human iPS Cell-Derived Neural Cells with an Artificial Nerve Conduit Leads to Cellular Retention in the Transplanted Area and Improves Motor Function in a Mouse Spinal Cord Injury Model (2019)
  • Author(s): Tomochika K, Arimitsu N, Murayama MA, Hirotsu C, Nagata K, Takai K, Shimizu J, Akazawa T, Torii Y, Umehara T, Iinuma M, Niki H, Suzuki N.
  • Journal Title: Journal of St. Marianna University Volume: 10 Issue: 2 Pages: 27-37
  • DOI: 10.17264/stmarieng.10.27
  • NAID: 130007791218
  • ISSN: 2185-1336, 2189-0277
  • 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 / Open Access
• [Journal Article] Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis (2018)
  • Author(s): Maruyama Tomohiro、Baba Takashi、Maemoto Yuki、Hara-Miyauchi Chikako、Hasegawa-Ogawa Minami、Okano Hirotaka James、Enda Yuki、Matsumoto Kei、Arimitsu Nagisa、Nakao Kazuki、Hamamoto Hiroshi、Sekimizu Kazuhisa、Ohto-Nakanishi Takayo、Nakanishi Hiroki、Tokuyama Takeshi、Yanagi Shigeru、Tagaya Mitsuo、Tani Katsuko
  • Journal Title: Cell Death & Disease Volume: 9 Issue: 8 Pages: 797-811
  • DOI: 10.1038/s41419-018-0815-3
  • Peer Reviewed / Open Access
• [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] 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] MOTOR FUNCTION RECOVERY IN HEMIPLEGIC MICE AFTER NEURAL STEM / PROGENITOR CELLS TRANSPLANTATION (2019)
  • Author(s): Nagisa Arimitsu, Kenji Takai, Chieko Hirotsu, Jun Shimizu and Noboru Suzuki
  • Organizer: International society for stem cell research 2019 annual meeting
  • Int'l Joint Research
• [Presentation] 完全離断脊髄損傷マウスモデルに対する神経再生誘導チューブ併用ヒトiPS細胞由来神経幹/前駆細胞移植の検討 (2019)
  • Author(s): 友近顕, 有光なぎさ, 廣津千恵子, 高井憲治, 村山正承, 赤澤努, 梅原亮, 飯沼雅央, 清水潤, 仁木 久照, 鈴木登
  • Organizer: 第34回日本整形外科学会基礎学術集会
• [Presentation] NEURAL REGENERATION MECHANISMS IN TRANSPLANTATION OF NEURONAL CELLS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS WITH THE EFFECT OF THEIR PARACRINE SECRETION. (2018)
  • Author(s): Nagisa Arimitsu, Jun Shimizu, Kenji Takai, Naruyoshi Fujiwara, Chieko Hirotsu, Yoko Okada and Noboru Suzuki
  • Organizer: International society for stem cell research 14th annual meeting
  • Int'l Joint Research
• [Presentation] Neural regeneration after transplantation of Neuronal cell sheet of cortical motor neuron phenotype. (2018)
  • Author(s): Nagisa Arimitsu-Nakata, Chieko Hirotsu,Kenji Takai, Jun Shimizu,Naruyoshi Fujiwara, Yoko Okada,Noboru Suzuki
  • Organizer: the 5th TERMIS-WC 2018
  • Int'l Joint Research
• [Presentation] Reelin Signal Activation is Associated With Motor Function Recovery in the Neuron Transplantation of Hemiplegic Mice. (2018)
  • Author(s): Nagisa Arimitsu, Jun Shimizu, Kenji Takai, Naruyoshi Fujiwara , Chieko Hirotsu, Yoko Okada , and Noboru Suzuki.
  • Organizer: the 51st Winter Conference on Brain Research (WCBR) . Whistler Canada 14-19 January 2018.
  • Int'l Joint Research