Establishment of the stem cell transplantation therapy by MUSE for moyamoya disease

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26462150
• Research Institution: Tohoku University
• Principal Investigator: 藤村 幹 東北大学, 医学系研究科, 准教授 (00361098)
• Co-Investigator(Kenkyū-buntansha): 冨永 悌二 東北大学, 医学系研究科, 教授 (00217548) ; 新妻 邦泰 東北大学, 医学系研究科, 助教 (10643330) ; 坂田 洋之 東北大学, 医工学研究科, 助教 (80722305)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: もやもや病 / 血管新生 / 幹細胞移植 / RNF213 / MUSE細胞

Outline of Annual Research Achievements

もやもや病に対する間接血行再建術における多能性幹細胞MUSE細胞を用いた血管新生促進の概念実証を目的に以下の検討を継続して行った。マウス/ラットに対する片側総頚動脈閉塞と二期的対側内頚動脈閉塞による慢性脳虚血誘導を再確認した。本モデルに間接血行再建術を追加施行し、脳表に接着させた側頭筋から虚血脳に向かう血管新生を確認した。さらに免疫組織染色、Western blot法による側頭筋ならびに虚血脳における血管新生因子の誘導を確認した。もやもや病疾患感受性遺伝子RNF213の脳虚血後の発現動態についてもマウス一過性前脳虚血モデルを用いて検証し、遅発性神経細胞死を呈する海馬CA1領域神経細胞におけるRNF213誘導を確認した。もやもや病により近い病態下での実験系確率を目的に行う目的で、疾患感受性遺伝子RNF213欠損マウス(RNF213 KO)に免疫負荷を行い高感度MRAにて脳血管を経時的に観察した。免疫負荷を行ったRNF213 KOで脳虚血後の血管新生促進は認めなかったが、RNF213 KOにおいては制御型T細胞の誘導抑制が明らかとなり免疫寛容の破綻が示唆された（Kanoke et al. Brain Res 2016）。
以上より慢性脳虚血と間接血行再建術モデルを用いて血管新生が再現性をもって誘導可能であり、血管新生因子の誘導を伴うことが確認された。
RNF213 KOにおいてもやもや病の病態に類似した免疫能異常が示唆されたことにより、病態評価を行う上での本遺伝子変異マウスを用いた検討は有効と考えられた。尚、MUSE細胞については培養したヒト間葉系幹細胞に対して、SSEA-3/CD105抗体を用いたMACSによる分離を行い効率良いMUSE細胞の分離方法を確率し、MUSE細胞を用いたもやもや病を模擬した動物モデルにおける血管新生促進の検証を推進している。

Research Products

• [Journal Article] De novo development of moyamoya disease in an adult female with a genetic variant of the RNF-213 gene: case report (2017)
  • Author(s): Tashiro R, Fujimura M, Niizuma K, Endo H, Sakata H, Sato-Maeda M, Tominaga T
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 26 Pages: e8-11
  • DOI: 10.1016/j.jstrokecerebrovasdis.2016.09.035.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Uneven cerebral hemodynamic change as a cause of neurological deterioration in the acute stage after direct revascularization for moyamoya disease: Cerebral hyperperfusion and remote ischemia caused by the 'watershed shift' (2017)
  • Author(s): Tu XK, Fujimura M, Rashad S, Mugikura S, Sakata H, Niizuma K, Tominaga T
  • Journal Title: Neurosurg Rev Volume: - Pages: -
  • DOI: 10.1007/s10143-017-0845-9
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Sequel of Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan (2017)
  • Author(s): Mugikura S, Fujimura M, Takahashi S, Takase K
  • Journal Title: Radiology Volume: - Pages: -
  • Peer Reviewed
• [Journal Article] Implications of “off-label” (unapproved) use of acetazolamide in the management of moyamoya in Japan (2016)
  • Author(s): Mugikura S, Fujimura M, Takahashi S
  • Journal Title: Radiology Volume: 279 Pages: 652-653
  • DOI: 10.1148/radiol.2016152305.
  • Peer Reviewed
• [Journal Article] Long-term follow-up of pediatric Moyamoya disease treated by combined direct-indirect revascularization surgery: Single institute experience with surgical and perioperative management (2016)
  • Author(s): Rashad S, Fujimura M, Niizuma K, Endo H, Tominaga T
  • Journal Title: Neurosurg Rev Volume: 39 Pages: 615-623
  • DOI: 10.1007/s10143-016-0734-7.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease (2016)
  • Author(s): Kanoke A, Fujimura M, Niizuma K, Fujimura T, Kakizaki A, Ito A, Sakata H, Sato-Maeda M, Kure S, Tominaga T
  • Journal Title: Brain Res Volume: 1642 Pages: 1-9
  • DOI: 10.1016/j.brainres.2016.03.009.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Brain stem infarction due to basilar artery dissection in a patient with moyamoya disease four years after successful bilateral revascularization surgeries (2016)
  • Author(s): Abe T, Fujimura M, Mugikura S, Endo H, Tominaga T
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 25 Pages: e76-82
  • DOI: 10.1016/j.jstrokecerebrovasdis.2016.03.024.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The pathophysiology of moyamoya disease: an update (2016)
  • Author(s): Bang OY, Fujimura M, Kim SK
  • Journal Title: J Stroke Volume: 18 Pages: 12-20
  • DOI: 10.5853/jos.2015.01760.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Moyamoya disease (2016)
  • Author(s): Fujimura M, Bang OY, Kim JS
  • Journal Title: Front Neurol Neurosci Volume: 40 Pages: 204-220
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Efficacy of direct/indirect combined revascularization surgery for Moyamoya disease: surgical indication, microsurgical techniques, and perioperative care (2017)
  • Author(s): Miki Fujimura
  • Organizer: 40th Annual Meeting of Egyptian Society of Neurological Surgeons
  • Place of Presentation: Giza, Egypt
  • Year and Date: 2017-03-21 – 2017-03-24
  • Int'l Joint Research / Invited
• [Presentation] Management of intracranial aneurysms; Microsurgical clipping as a standard procedure and application of EC-IC bypass for complex aneurysms (2017)
  • Author(s): Miki Fujimura
  • Organizer: 40th Annual Meeting of Egyptian Society of Neurological Surgeons
  • Place of Presentation: Giza, Egypt
  • Year and Date: 2017-03-21 – 2017-03-24
  • Int'l Joint Research / Invited
• [Presentation] もやもや病に対する血行再建術：術式選択と周術期病態の現状と課題 (2017)
  • Author(s): 藤村幹
  • Organizer: 第46回 日本脳卒中の外科学会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2017-03-16 – 2017-03-18
• [Presentation] もやもや病 (2017)
  • Author(s): 藤村幹
  • Organizer: 第42回日本脳卒中学会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2017-03-16 – 2017-03-18
  • Invited
• [Presentation] 成人もやもや病に対する直接間接複合バイパス術：脳循環画像に基づいた周術期管理の効果とpitfall (2016)
  • Author(s): 藤村幹
  • Organizer: 第５９回日本脳循環代謝学会
  • Place of Presentation: あわぎんホール、徳島
  • Year and Date: 2016-11-11 – 2016-11-12
• [Presentation] Moyamoya disease, Update (2016)
  • Author(s): Miki Fujimura
  • Organizer: Pierre Lasjaunias Neurovascular Educational Team Course. (PLANET). 2016
  • Place of Presentation: Akasaka Park Building, Tokyo
  • Year and Date: 2016-10-22 – 2016-10-27
  • Int'l Joint Research / Invited
• [Presentation] もやもや病に対する直接間接・複合頭蓋外内バイパス術の長期治療成績：小児例と成人例の比較検討 (2016)
  • Author(s): 藤村幹
  • Organizer: 日本脳神経外科学会 第75回学術総会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2016-09-29 – 2016-10-01
• [Presentation] Complication avoidance in revascularization surgery for moyamoya disease: significance of intraoperative decision making (2016)
  • Author(s): Miki Fujimura
  • Organizer: The 13th Japanese and Korean Joint Conference on Surgery for Cerebral Stroke
  • Place of Presentation: Busan, Korea
  • Year and Date: 2016-09-22 – 2016-09-24
  • Int'l Joint Research / Invited
• [Presentation] 疾患感受性遺伝子RING finger protein (RNF)-213遺伝子変異マウスを用いたもやもや病病態解明の試み (2016)
  • Author(s): 藤村幹
  • Organizer: 第17回日本分子脳神経外科学会
  • Place of Presentation: 帝京大学板橋キャンパス、東京
  • Year and Date: 2016-08-26 – 2016-08-27
  • Invited
• [Presentation] 出血発症もやもや病の治療戦略 (2016)
  • Author(s): 藤村幹
  • Organizer: 第36回日本脳神経外科コングレス総会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2016-05-20 – 2016-05-22
  • Invited