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

• Project/Area Number: 26462150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Tohoku University
• Principal Investigator: Miki Fujimura 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
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: moyamoya disease / もやもや病 / 血管新生 / 幹細胞移植 / RNF213 / MUSE細胞 / 再生療法

Outline of Final Research Achievements

The objective of this study was to establish stem cell transplantation therapy using pluripotent MUSE cells for the patients with moyamoya disease. Mice and rats were subjected to chronic cerebral ischemia and then underwent indirect pial synangiosis, in a consistent situation of indirect bypass for moyamoya disease. Two-staged carotid artery occlusion reproducibly provided chronic hypoperfusion and the development of pial synangiosis by our methods. To obtain more similar condition to moyamoya disease, we alternatively generated genetically-engineered mice of RNF213, a susceptibility gene for moyamoya disease. Spontaneous development of moyamoya disease was not evident in these mice, while RNF213-deficient mice demonstrated decreased ratio of regulatory T cells after immunologic adjuvant administration. Regarding MUSE cell preparation, using MUSE cells were successfully sorted by anti- SSEA-3/CD105 antibodies from cultured mesenchymal stromal cells.

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 Issue: 1 Pages: e8-e11
  • 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: - Issue: 3 Pages: 507-512
  • 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: -
  • Peer Reviewed
• [Journal Article] Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan. (2016)
  • Author(s): Mugikura S, Fujimura M, Takahashi S.
  • Journal Title: Radiology Volume: 279(2) Issue: 2 Pages: 652-3
  • 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 Issue: 4 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: in press 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 Issue: 6 Pages: 79-82
  • 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 Issue: 1 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
• [Journal Article] Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213, a susceptibility gene for moyamoya disease. (2016)
  • Author(s): Sato-Maeda M, Fujimura M, Kanoke A, Morita-Fujimura Y, Niizuma K, Tominaga T.
  • Journal Title: Brain Res Volume: 1630 Pages: 50-55
  • DOI: 10.1016/j.brainres.2015.10.055
  • Peer Reviewed / Acknowledgement Compliant
• [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: in press
  • Peer Reviewed / Int'l Joint Research / 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: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Required Knowledge for Stroke Specialists(11)Management of Moyamoya Disease (2015)
  • Author(s): 藤村幹、冨永悌二.
  • Journal Title: Neurological Surgery 脳神経外科 Volume: 43 Issue: 6 Pages: 557-565
  • DOI: 10.11477/mf.1436203073
  • ISSN: 0301-2603, 1882-1251
  • Year and Date: 2015-06-10
  • Peer Reviewed
• [Journal Article] Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. (2015)
  • Author(s): Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, Morita-Fujimura Y, Kure S, and Tominaga T.
  • Journal Title: Brain Res Volume: 1624 Pages: 497-505
  • DOI: 10.1016/j.brainres.2015.07.039
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Local vasogenic edema without cerebral hyperperfusion after direct revascularization surgery for moyamoya disease. (2015)
  • Author(s): Sakata H, Fujimura M, Mugikura S, Sato K, Tominaga T.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Issue: 7 Pages: 179-184
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.050
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Significance of Cerebral Blood Flow Analysis in the Acute Stage after Revascularization Surgery for Moyamoya Disease (2015)
  • Author(s): Fujimura M, Tominaga T.
  • Journal Title: Neurologia medico-chirurgica Volume: 55 Issue: 10 Pages: 775-781
  • DOI: 10.2176/nmc.ra.2015-0063
  • NAID: 130005103346
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diagnosis of Moyamoya Disease: International Standard and Regional Differences (2015)
  • Author(s): Fujimura M, Tominaga T.
  • Journal Title: Neurologia medico-chirurgica Volume: 55 Issue: 3 Pages: 189-193
  • DOI: 10.2176/nmc.ra.2014-0307
  • NAID: 130004725003
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Current Status of Revascularization Surgery for Moyamoya Disease: Special Consideration for Its ‘Internal Carotid-External Carotid (IC-EC) Conversion’ as the Physiological Reorganization System (2015)
  • Author(s): Fujimura M, Tominaga T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 236 Issue: 1 Pages: 45-53
  • DOI: 10.1620/tjem.236.45
  • NAID: 130005069562
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] もやもや病に対する血行再建術後・過灌流に対するミノサイクリンを用いた周術期管理の現状と問題点. (2015)
  • Author(s): 藤村幹、新妻邦泰、遠藤英徳、佐藤健一、井上敬、冨永悌二.
  • Journal Title: 脳卒中の外科 Volume: 43 Pages: 136-140
  • NAID: 130005072756
  • Peer Reviewed
• [Journal Article] Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. (2015)
  • Author(s): Ito A, Fujimura M, Niizuma K, Kanoke A, Sakata H, Morita-Fujimura Y, Kikuchi A, Kure S, Tominaga T.
  • Journal Title: Brain Res Volume: 16 Pages: 310-320
  • DOI: 10.1016/j.brainres.2014.11.014
  • Peer Reviewed
• [Journal Article] Quantitative analysis of early postoperative cerebral blood flow contributes to the prediction and diagnosis of cerebral hyperperfusion syndrome after revascularization surgery for moyamoya disease (2015)
  • Author(s): FUJIMURA M, Niizuma K, Endo H, Sato K, Inoue T, Shimizu H, Tominaga T
  • Journal Title: Neurol Res Volume: 37 Issue: 2 Pages: 131-138
  • DOI: 10.1179/1743132814y.0000000432
  • Peer Reviewed
• [Journal Article] Genetics and Biomarkers of Moyamoya Disease: Significance of RNF213 as a susceptibility gene (2014)
  • Author(s): FUJIMURA M, Sonobe S, Nishijima Y, Niizuma K, Sakata H, Kure S, Tominaga T
  • Journal Title: J Stroke Volume: 16 Pages: 65-72
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213 : a susceptibility gene for moyamoya disease (2014)
  • Author(s): Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, Kikuchi A, Arai-Ichinoi N, Kure S, T ominaga T
  • Journal Title: Brain Res Volume: 1552 Pages: 64-71
  • DOI: 10.1016/j.brainres.2014.01.011
  • Peer Reviewed
• [Journal Article] Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. (2014)
  • Author(s): Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, Kure S, Tominaga T.
  • Journal Title: Neuroreport Volume: 1552 Issue: 18 Pages: 64-71
  • DOI: 10.1097/wnr.0000000000000289
  • Peer Reviewed
• [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
  • 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
  • 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
• [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
  • 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
• [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
  • 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
• [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
  • 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
  • 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
  • Invited
• [Presentation] Current status of revascularization surgery for moyamoya disease; Special consideration for ‘IC-EC conversion’ as its physiological reorganization system. (2016)
  • Author(s): Fujimura M, Tominaga T
  • Organizer: The 11st Asian Congress of Neurological Surgeons.
  • Place of Presentation: Surabaya, Indonesia
  • Year and Date: 2016-03-10
  • Int'l Joint Research / Invited
• [Presentation] Efficacy of direct/indirect combined revascularization surgery for moyamoya disease: significance of CBF analysis in the acute stage. (2016)
  • Author(s): Fujimura M, Tominaga T
  • Organizer: The 12th International Conference on Cerebrovascular Surgery.
  • Place of Presentation: Mumbai, India
  • Year and Date: 2016-02-26
  • Int'l Joint Research / Invited
• [Presentation] Microsurgery for aneurysms. (2015)
  • Author(s): Fujimura M
  • Organizer: 1st Walter E. Dandy Neurosurgical Society Quadrennial Meeting.
  • Place of Presentation: Dubai, UAE
  • Year and Date: 2015-11-18
  • Int'l Joint Research / Invited
• [Presentation] 小児もやもや病に対する直接間接複合バイパス術：長期治療成績 (2015)
  • Author(s): 藤村幹、冨永悌二
  • Organizer: 第27回日本脳循環代謝学会
  • Place of Presentation: 富山（富山国際会議場）
  • Year and Date: 2015-10-30
• [Presentation] Genetics of moyamoya disease: Recent study using genetic engineered mice of RNF213; A moyamoya disease susceptibility gene (2015)
  • Author(s): Fujimura M, Kure S, Tominaga T
  • Organizer: The 7th Japanese-Korean Joint Stroke Conference
  • Place of Presentation: Busan, Korea
  • Year and Date: 2015-10-22
  • Int'l Joint Research / Invited
• [Presentation] もやもや病の病態解明：もやもや病疾患感受性遺伝子RNF213遺伝子変異マウスを用いた検討. (2015)
  • Author(s): 藤村幹、新妻邦泰、園部真也、伊藤明、鹿毛淳史、呉繁夫、冨永悌二.
  • Organizer: 日本脳神経外科学会第74回学術総会.
  • Place of Presentation: 札幌（ロイトン札幌）
  • Year and Date: 2015-10-14
  • Invited
• [Presentation] もやもや病に対する血行再建術：術中ICG蛍光血管撮影と術後脳循環画像に基づいた周術期管理の現状と課題. (2015)
  • Author(s): 藤村幹
  • Organizer: 日本脳神経外科学会第74回学術総会.
  • Place of Presentation: 札幌（ロイトン札幌）
  • Year and Date: 2015-10-14
  • Invited
• [Presentation] Prophylactic blood pressure lowering with intravenous minocycline administration as secure and effective postoperative management after revascularization surgery for moyamoya disease. (2015)
  • Author(s): Fujimura M, Niizuma K, Endo H, Sakata H, Tominaga T.
  • Organizer: 15th Interim Meeting of the World Federation of Neurological Societies.
  • Place of Presentation: Rome, Italy
  • Year and Date: 2015-09-08
  • Int'l Joint Research
• [Presentation] Outcome of revascularization surgery for elderly patients with moyamoya disease over the age of 60 years: Single institute experience. (2015)
  • Author(s): Fujimura M, Niizuma K, Endo H, Sakata H, Tominaga T.
  • Organizer: 4th International Moyamoya Meeting.
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2015-07-02
  • Int'l Joint Research
• [Presentation] もやもや病の治療戦略. (2015)
  • Author(s): 藤村幹、冨永悌二
  • Organizer: 第35回日本脳神経外科コングレス総会.
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2015-05-08
  • Invited
• [Presentation] 脳血管外科における生体吸収性プレート/チタンプレートのハイブリッド使用による頭蓋骨形成の試み. (2015)
  • Author(s): 藤村幹
  • Organizer: 第8回日本整容脳神経外科研究会
  • Place of Presentation: 大阪（ナレッジキャピタル）
  • Year and Date: 2015-04-04
  • Invited
• [Presentation] もやもや病術後急性期のMRI・SPECT画像所見に基づいた周術期管理 (2015)
  • Author(s): 藤村幹
  • Organizer: 第44回日本神経放射線学会
  • Place of Presentation: 名古屋キャッスルホテル（名古屋市）
  • Year and Date: 2015-03-05 – 2015-03-07
  • Invited
• [Presentation] Current status of revascularization surgery for adult Moyamoya disease in Japan (2015)
  • Author(s): Miki Fujimura
  • Organizer: 8ｔｈ Catholic Intenational Neurosurgery Update
  • Place of Presentation: ソウル、韓国
  • Year and Date: 2015-02-27 – 2015-03-01
  • Invited
• [Presentation] Role of EC-IC bypass in cerebrovascular surgery: special consideration for moyamoya disease (2014)
  • Author(s): Miki Fujimura
  • Organizer: The 11th International Conference on Cerebrovascular Surgery 2014
  • Place of Presentation: ジャカルタ、インドネシア
  • Year and Date: 2014-12-10 – 2014-12-15
• [Presentation] もやもや病に対する血行再建術：手術適応と周術期管理の要点 (2014)
  • Author(s): 藤村幹
  • Organizer: 第26回日本脳循環代謝学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山市）
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] もやもや病に対する直接間接複合バイパス術：術中のdecision makingと周術期管理についての検討 (2014)
  • Author(s): 藤村幹
  • Organizer: 日本脳神経外科学会 第73回学術総会
  • Place of Presentation: 新高輪プリンスホテル（東京）
  • Year and Date: 2014-10-08 – 2014-10-11
• [Presentation] もやもや病に対する血行再建術における脳循環画像の意義 (2014)
  • Author(s): 藤村幹
  • Organizer: 第33回The M.Fuji Worksop on CVD 参加
  • Place of Presentation: ホテルメトロポリタン盛岡（盛岡市）
  • Year and Date: 2014-08-29 – 2014-08-30
• [Presentation] 血管吻合の基本手技(ハンズオン血管吻合コース） (2014)
  • Author(s): 藤村幹
  • Organizer: 第34回 日本脳神経外科コングレス総会参加
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-05-15 – 2014-05-17
• [Book] もやもや病. 脳神経外科学 改訂12版 太田富雄編 (2016)
  • Author(s): 藤村幹
  • Total Pages: 2870
  • Publisher: 金芳堂、京都
• [Book] もやもや病. 脳卒中治療ガイドライン2015 (2015)
  • Author(s): 藤村幹
  • Total Pages: 337
  • Publisher: 協和企画、東京
• [Book] 太田富男監修「脳神経外科学」（第12判 10章 脳血管障害 §4 もやもや病 (2015)
  • Author(s): 藤村幹
  • Publisher: 金芳堂