Analysis of the recovery mechanism of cell therapy to perinatal white matter injury

• Project/Area Number: 18K07882
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya City University
• Principal Investigator: Hida Hideki 名古屋市立大学, 医薬学総合研究院(医学), 教授 (00305525)
• Co-Investigator(Kenkyū-buntansha): 清水 健史 名古屋市立大学, 医薬学総合研究院(医学), 講師 (60398237)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 細胞療法 / 低酸素虚血性白質障害 / オリゴデンドロサイト前駆細胞 / IGF-2 / 分化抑制 / 髄鞘形成 / 豊かな環境飼育 / 皮質内微小電気刺激 / 髄鞘化解析モデル / FRET法 / サイクロスポリン / カーボンナノファイバー / 細胞移植 / 低酸素性虚血性白質障害 / インスリン様成長因子２型 / 低酸素虚血性白質傷害

Outline of Final Research Achievements

Our final purpose is the establishment of cell therapy to perinatal white matter injury (PWMI). To establish cell therapy to a PWMI model rat using oligodendrocyte progenitor (OPC), we revealed that grafted OPC survived in the corpus callosum (CC) until 8week after the graft, and IGF-2 that is upregulated in the model brain exhibited trophic effect on cultured OPCs. Furthermore, to analyze the mechanism of the survival of the grafted cells in the CC, we performed several experiments focusing on the relationship between myelination and the recovery of the disturbed function: the analysis of myelin formation by FRET following to the construction of in vitro myelination system, and the analysis of the effect of environmental enrichment during the period of the development on the PWMI model.

Academic Significance and Societal Importance of the Research Achievements

低酸素虚血性白質障害に対する細胞療法の確立という最終目的に向け、動物実験レベルでの課題を抽出し、そのメカニズムの解析にチャレンジしている。本研究からIGF-2が培養OPCに対し生理活性を示すことも初めて明らかにした。また病態脳では移植OPCの分化が抑制されている事実を示し、最終目的に向けた新たな課題を明らかにした。加えて移植細胞の生着メカニズムを髄鞘形成機構の解析や発育期の飼育環境による相加的効果という多角的な解析を進めているのが特徴である。難題を一歩ずつ解決し臨床応用にまで繋がれば意義が大きい。

Research Products

• [Journal Article] Temporal inversion of the acid-base equilibrium in newborns: an observational study (2021)
  • Author(s): Mizutani Yuko、Kinoshita Masahiro、Lin Yung-Chieh、Fukaya Satoko、Kato Shin、Hisano Tadashi、Hida Hideki、Iwata Sachiko、Saitoh Shinji、Iwata Osuke
  • Journal Title: PeerJ Volume: 9 Pages: e11240-e11240
  • DOI: 10.7717/peerj.11240
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tension sensor based on fluorescence resonance energy transfer reveals fiber diameter-dependent mechanical factors during myelination (2021)
  • Author(s): Shimizu T, Murakoshi H, Matsumoto H, Ichino K, Hattori A, Ueno S, Ishida A, ytajiri N, Hida H.
  • Journal Title: Front Cell Neurosci Volume: 15 Pages: 685044-685044
  • DOI: 10.3389/fncel.2021.685044
  • Peer Reviewed / Open Access
• [Journal Article] Reduction of acetylcholine ion the hippocampus of hippocampus cholinergic neurostimulating peptide precursor protein knockout mice (2021)
  • Author(s): Kondo-Takuma Y, Mizuno M, Tsuda Y, madokoro Y, Suzuki K, Sato T, takase H, Uchida Y, Adachi KI, Hida H, Borlongan CV, Matsukawa N.
  • Journal Title: Sci Rep Volume: 11(1) Issue: 1
  • DOI: 10.1038/s41598-021-01667-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy (2020)
  • Author(s): Suzuki Toshihiko、Sato Yoshiaki、Kushida Yoshihiro、Tsuji Masahiro、Wakao Shohei、Ueda Kazuto、Imai Kenji、Iitani Yukako、Shimizu Shinobu、Hida Hideki、Temma Takashi、Saito Shigeyoshi、Iida Hidehiro、Mizuno Masaaki、Takahashi Yoshiyuki、Dezawa Mari、Borlongan Cesar V、Hayakawa Masahiro
  • Journal Title: Journal of Cerebral Blood Flow & Metabolism Volume: 0 Issue: 7 Pages: 1-14
  • DOI: 10.1177/0271678x20972656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transplanted oligodendrocyte progenitor cells survive in the brain of a rat neonatal white matter injury model but less mature in comparison with the normal brain (2020)
  • Author(s): Ogawa S, Hagiwara M, Misumi S, Tajiri N, Shimizu T, Ishida A, Suzumori N, Mayumi Sugiura-Ogasawara M, Hida H
  • Journal Title: Cell Transplantation Volume: 29 Pages: 1-10
  • DOI: 10.1177/0963689720946092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Social defeat stress in adolescent mice induces depressive-like behaviors with reduced oligodendrogenesis (2020)
  • Author(s): Shimizu T, Ishida A, Hagiwara M, Ueda Y, Hattori A, Tajiri N, Hida H
  • Journal Title: Neuroscience Volume: 443 Pages: 218-232
  • DOI: 10.1016/j.neuroscience.2020.07.002
  • Peer Reviewed / Open Access
• [Journal Article] Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice. (2019)
  • Author(s): Madokoro Y, Yoshino Y, Kato D, Sato T, Mizuno M, Kanamori T, Shimazawa M, Hida H, Hara H, Yoshida M, Borlongan CV, Ojika K, Matsukawa N.
  • Journal Title: Int J Mol Sci. Volume: 20(21) Issue: 21 Pages: 1-17
  • DOI: 10.3390/ijms20215367
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats (2019)
  • Author(s): Ishida A, Kobayashi K, Ueda Y, Shimizu T, Tajiri N, Isa T, Hida H
  • Journal Title: J Neurosci Volume: 39 Issue: 37 Pages: 7306-7320
  • DOI: 10.1523/jneurosci.0649-19.2019
  • Peer Reviewed / Open Access
• [Journal Article] Alterations of both dendrite morphology and weaker electrical responsiveness in the cortex of hip area occur before rearrangement of the motor map in neonatal white matter injury model rats (2018)
  • Author(s): Ueda Y, Bando Y, Misumi S, Ogawa S, Ishida A, Jung CG, Shimizu T, Hida H
  • Journal Title: Frontiers in Neurology Volume: 9 Pages: 443-443
  • DOI: 10.3389/fneur.2018.00443
  • Peer Reviewed / Open Access
• [Journal Article] Monosodium glutamate ingestion during the development period reduces aggression mediated by the vagus nerve in a rat model of attention deficit hyperactivity disorder (2018)
  • Author(s): Nishigaki R, Yokoyama Y, Shimizu Y, Marumoto R, Misumi S, Ueda Y, Ishida A, Shibuya Y, Hida H
  • Journal Title: Brain Research Volume: 1690 Pages: 40-50
  • DOI: 10.1016/j.brainres.2018.04.006
  • Peer Reviewed / Open Access
• [Presentation] Elucidation of damaged brain regeneration mechanism by cell therapy and enriched environment for neonatal white matter injury (2021)
  • Author(s): Naoki Tajiri Shino Ogawa Atsunori Hattori, Ayano Otani, Shinya Ueno, Takeshi Shimizu Hideki Hida
  • Organizer: 日本生理学会2021 名古屋
  • Invited
• [Presentation] Transplantation of oligodendrocyte progenitor cells with cyclosporine A protects from neonatal white matter injury-induced motor and histological impairments (2021)
  • Author(s): Ryotaro Anazawa, Haruka Sugiura, Ayano Ohtani, Shino Ogawa, Naoki Tajiri, Hideki Hida
  • Organizer: 日本生理学会2021 名古屋
• [Presentation] New assay system to detect mechanical force in myelinating oligodendrocytes using a tension sensor probe (2020)
  • Author(s): Takeshi Shimizu, Hideji Murakoshi, Hidetoshi Matsumoto, Akimasa Ishida, Naoki Tajiri, Hideki Hida
  • Organizer: 日本神経科学会2020
• [Presentation] Intracerebral grafts of oligodendrocyte progenitor cells attenuate behavioral deficits in neonatal white matter injury model of rats (2020)
  • Author(s): Naoki Tajiri Shino Ogawa Atsunori Hattori Akimasa Ishida Takeshi Shimizu Hideki Hida
  • Organizer: 日本神経科学会2020
• [Presentation] Grafted oligodendrocyte progenitors can differentiate into oligodendrocyte without immunosuppressant but mature less in the corpus callosum of a rat neonatal white matter injury model (2020)
  • Author(s): Hideki Hida, Shino Ogawa, Mutsumi Hagiwara, Naoki Tajiri, Takeshi Shimizu,
  • Organizer: FENS 2020
  • Int'l Joint Research
• [Presentation] Enriched environment after hypoxic-ischemia normalizes dendrite morphology of the cortex layer II/III accompanied with oligodendrocyte differentiation in rat of neonatal white matter injury (2020)
  • Author(s): Hideki Hida, Atsunori Hattori, Takeshi Shimizu, Naoki Tajiri
  • Organizer: 日本神経化学会2020 八王子
• [Presentation] New assay system to detect mechanical force in myelinating oligodendrocytes using a tension sensor probe (2020)
  • Author(s): Takeshi Shimizu, Hideji Murakoshi, Hidetoshi Matsumoto, Akimasa Ishida, Naoki Tajiri, Hideki Hida
  • Organizer: 日本生理学会
• [Presentation] Functional recovery by cell grafts of oligodendrocyte progenitor cells to neonatal white matter injury model in rats (2020)
  • Author(s): Naoki Tajiri, Atsunori Hattori, Shino Ogawa, Akimasa Ishida, Takeshi Shimizu, Hideki Hida
  • Organizer: 日本生理学会
• [Presentation] Enriched environment affects neuronal dendrite morphology and oligodendrocyte differentiation in neonatal white matter injury model (2020)
  • Author(s): Atsunori Hattori, Naoki Tajiri, Yoshitomo Ueda, Akimasa Ishida, Takeshi Shimizu, Hideki Hida
  • Organizer: 日本生理学会
• [Presentation] Chronic social defeat stress to adolescent mice reduces anxiety-like behavior with reduced oligodendrocyte generation (2019)
  • Author(s): Takeshi Shimizu, Akimasa Ishida, Naoki Tajiri, Hideki Hida
  • Organizer: 日本神経科学会
• [Presentation] Chronic social defeat stress to adolescent mice induces anxiety-like behavior with reduced oligodendrogenesis (2019)
  • Author(s): Atsunori Hattori, Yoshitomo Ueda, Naoki Tajiri, Shino Ogawa, Akimasa Ishida, Takeshi Shimizu, Hideki Hida
  • Organizer: 日本神経科学会
• [Presentation] Chronic social defeat stress to adolescent mice induces anxiety-like behavior with reduced oligodendrogenesis (2019)
  • Author(s): Takeshi Shimizu, Akimasa Ishida, Naoki Tajiri, Hideki Hida
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Functional recovery by enriched environment in neonatal white matter injury: evidence from morphological and electrophysiological assessments (2019)
  • Author(s): Atsunori Hattori, Yoshitomo Ueda, Naoki Tajiri, Hideki Hida
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Enriched environment during the period of development attenuates hindlimb dysfunction in neonatal white matter injury mode (2019)
  • Author(s): Tajiri N, Hattori A, Ueda Y, Ogawa S, Ishida, A, Shimizu T, Hida H
  • Organizer: 第96回日本生理学会 / FAOPS 2019
  • Int'l Joint Research
• [Presentation] Insulin-like growth factor-2, an increasing factor in neonatal white matter injury brain, promotes the differentiation of oligodendrocyte progenitor cells in vitro (2018)
  • Author(s): Ogawa S, Hagiwara M, Shimizu T, Ueda, Y, Misumi S, Ishida A, Hida H.
  • Organizer: ASNTR-25/INTR-15
  • Int'l Joint Research
• [Presentation] 低酸素虚血性白質障害モデルへのオリゴデンドロサイト前駆細胞移植におけるIGF-2の作用 (2018)
  • Author(s): 小川紫野、鈴森伸宏、杉浦真弓、飛田秀樹
  • Organizer: 第54回日本周産期新生児学会
• [Presentation] 発育期の豊かな環境飼育が新生児低酸素虚血性白質障害モデルラットに与える影響 (2018)
  • Author(s): 服部篤紀，田尻直輝，上田佳朋, 小川紫野, 石田章真、清水健史、飛田秀樹
  • Organizer: 中部日本生理学会
• [Presentation] Interaction between cortico-rubral tract and cortico-reticular tract in rehabilitation-induced functional recovery after capsular hemorrhage (2018)
  • Author(s): Ishida A, K. Kobayashi K, Isa T, Hida H
  • Organizer: Society for Neuroscience 2018
  • Int'l Joint Research