Effects of Cell Therapy for Cerebral Infarction on Stem Cell Niches

2011 Fiscal Year Final Research Report

• Project/Area Number: 21500359
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hyogo Medical University
• Principal Investigator: MATSUYAMA Tomohiro 兵庫医科大学, 医学部, 教授 (10219529)
• Co-Investigator(Kenkyū-buntansha): KASHIWAMURA Shin-ichiro 兵庫医科大学, 医学部, 准教授 (00185761) ; NAKAGOMI Takayuki 兵庫医科大学, 医学部, 講師 (80434950)
• Co-Investigator(Renkei-kenkyūsha): TAGUCHI Akihiko (財)先端医療振興財団先端医療センター, 再生医療研究部, 部長 (10359276)
• Project Period (FY): 2009 – 2011
• Keywords: 幹細胞生物学 / 再生 / 修復 / Pericyte

Research Abstract

In this study, we attributed to explore the characteristics of the induced-neural stem/progenitor cells(iNSPCs) with focusing on the newly generated vascular cells as stem cell niche. We demonstrated that inflammatory cells including lymphocytes affected the post-stroke neurogenesis(J Neurosci Res 2010), and proliferation of iNSPCs was suppressed by endostatin or angiotensin. Bone-marrow derived mononuclear cells(BMMCs) promoted proliferation of endothelial cells with increasing generation of FGF, EGF, IGF and PDGF, suggesting the role on the maintenance of endothelial cells. In addition, BMMCs transplantation increased cerebral blood flow and improved brain function(Stem Cells 2010). Since iNSPCs are originated from the vascular pericytes(Stem Cell Dev 2011) and iNSPCs undergoes apoptosis by the activated lymphocytes(Cell Death Differ 2011), it is hypothesized that iNSPCs are influenced by inflammatory cells. These findings suggest that endothelial cells have an important role on the post-stroke neurogenesis and functional repair.

Research Products

• [Journal Article] Human umbilical cord provides a significant source of unexpanded mesenchymal stromal cells (2012)
  • Author(s): Kikuchi-Taura A, Taguchi A, Kanda T, Inoue T, Kasahara Y, Hirose H, Sato I, Matsuyama T, Nakagomi T, Yamahara K, Stern D, Ogawa H, Soma T.
  • Journal Title: Cytotherapy Volume: 14(4) Pages: 441-50
  • Peer Reviewed
• [Journal Article] Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke (2012)
  • Author(s): Takata M, Nakagomi T, Kashiwamura S, Nakano-Doi A, Saino O, Nakagomi N, Okamura H, Mimura O, Taguchi A, Matsuyama T.
  • Journal Title: Cell Death Differ Volume: 19(5) Pages: 756-67
  • Peer Reviewed
• [Journal Article] Cilostazol reduces the risk of hemorrhagic infarction after administration of tissue plasminogen activator in a murine stroke model (2011)
  • Author(s): Kasahara Y, Nakagomi T, Matsuyama T, Stern D, Taguchi A.
  • Journal Title: Stroke Volume: 43(2) Pages: 449-506
  • Peer Reviewed
• [Journal Article] Ischemia-induced neural stem/progenitor cells express pyramidal cell markers (2011)
  • Author(s): Clausen, M, Nakagomi T, Nakano-Doi A, Saino O, Takata M, Taguchi A, Luiten P, Matsuyama T.
  • Journal Title: NeuroReport Volume: 22 Pages: 789-794
  • Peer Reviewed
• [Journal Article] Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction (2011)
  • Author(s): Nakagomi T, Molnar Z, Nakano-Doi A, Taguchi A, Saino O, Kubo S, Clausen M, Yoshikawa H, Nakagomi N, Matsuyama T.
  • Journal Title: Stem Cells Dev Volume: 20 Pages: 2037-51
  • Peer Reviewed
• [Journal Article] Reduced ischemic brain injury by partial rejuvenation of bone marrow cells in aged rats (2011)
  • Author(s): Taguchi A, Zhu P, Cao F, Kikuchi-Taura A, Kasahara Y, Stern DM, Soma T, Matsuyama T, Hata R.
  • Journal Title: J Cereb Blood Flow Metab Volume: 31 Pages: 855-67
  • Peer Reviewed
• [Journal Article] Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction (2010)
  • Author(s): Nakano-Doi A, Nakagomi T, Fujikawa M, Nakagomi1 N, Kubo S, Lu S, Yoshikawa, H, Soma T, Taguchi A, Matsuyama T.
  • Journal Title: Stem Cells Volume: 28 Pages: 1292-1302
  • Peer Reviewed
• [Journal Article] Telmisartan suppresses cerebral injury in a murine model of transient focal ischemia (2010)
  • Author(s): Kasahara Y, Taguchi A, Uno H, Nakano A, Nakagomi T, Hirose H, Stern DM, Matsuyama T.
  • Journal Title: Brain Res Volume: 1340 Pages: 70-80
  • Peer Reviewed
• [Journal Article] A reproducible and simple model of permanent cerebral ischemia in CB-17 and SCID mice (2010)
  • Author(s): Taguchi A, Kasahara Y, Nakagomi T, Stern DM, Fukunaga M, Ishikawa M, Matsuyama T.
  • Journal Title: J Exp Stroke Transl Med Volume: 3 Pages: 28-33
  • Peer Reviewed
• [Journal Article] Immunodeficiency reduces neural stem/progenitor cell-apoptosis and enhances neurogenesis in the cerebral cortex after stroke (2010)
  • Author(s): Saino O, Taguchi A, Nakagomi T, Nakano-Doi A, Kashiwamura S, Doe N, Nakagomi N, Soma T, Yoshikawa H, Stern DM, Okamura H, Matsuyama T.
  • Journal Title: J Neurosci Res Volume: 88 Pages: 2385-97
  • Peer Reviewed
• [Journal Article] Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex (2010)
  • Author(s): Nakayama D, Matsuyama T, Ishibashi-Ueda H, Nakagomi T, Kasahara Y, Hirose H, Kikuchi-Taura A, Stern DM, Mori H, Taguchi A.
  • Journal Title: Eur J Neurosci Volume: 31 Pages: 90-8
  • Peer Reviewed
• [Journal Article] Endothelial cells support survival, proliferation and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction (2009)
  • Author(s): Nakagomi N, Nakagomi T, Kubo S, Nakano-Doi A, Saino O, Takata M, Yoshikawa H, Stern DM, Matsuyama T, Taguchi A.
  • Journal Title: Stem Cells Volume: 27 Pages: 2185-98
  • Peer Reviewed
• [Presentation] 急性期脳梗塞患者に対する自己骨髄単核球細胞投与の臨床試験 (2011)
  • Author(s): 田口明彦, 松山知弘, 長束一行
  • Organizer: 第23回日本脳循環代謝学会総会
  • Place of Presentation: 東京
  • Year and Date: 20111104-05
• [Presentation] 大脳皮質梗塞後に誘導される脳軟膜由来神経幹細胞の発見 (2011)
  • Author(s): 中込隆之, 土居亜紀子, 田片将士, 盧山, 立花久大, 土江伸誉, 田口明彦, 松山知弘
  • Organizer: 第23回日本脳循環代謝学会総会
  • Place of Presentation: 東京
  • Year and Date: 20111104-05
• [Presentation] 一過性脳虚血誘導性神経幹細胞の発現 (2011)
  • Author(s): 百田義弘, 中込隆之, 中野亜紀子, 田口明彦, 柴田啓貴, 田片将士, 塚本吉胤, 小谷順一郎, 松山知弘
  • Organizer: 第23回日本脳循環代謝学会総会
  • Place of Presentation: 東京
  • Year and Date: 20111104-05
• [Presentation] Bone marrow mononuclear cells improve sensory disturbance with promoting endogenous neurogenesis at the ipsilateral thalamus damaged after cortical infarction (2011)
  • Author(s): Nakano-Doi A, Doe N, Nakagomi T, Takata M, Lu S, Kanaoka S, Tachibana H, Taguchi A, Matsuyama T.
  • Organizer: The 34th Annual Meeting of the Japan Neuroscience Society, Neuro2011(第34回日本神経科学大会)
  • Place of Presentation: 横浜
  • Year and Date: 20110914-17
• [Presentation] 若齢ラット造血系幹細胞移植による老齢ラット微小循環障害の治療効果 (2011)
  • Author(s): 田口明彦, 笠原由紀子, 松山知弘, 朱鵬翔, 曹芳, 秦龍二
  • Organizer: 第36回日本脳卒中学会総会
  • Place of Presentation: 京都
  • Year and Date: 20110730-0801
• [Presentation] 出血性梗塞モデルマウスにおけるシロスタゾールの脳出血予防効果 (2011)
  • Author(s): 笠原由紀子, 松山知弘, 長束一行, 田口明彦
  • Organizer: 第36回日本脳卒中学会総会
  • Place of Presentation: 京都
  • Year and Date: 20110730-0801
• [Presentation] Prevention of alteplase-induced hemorrhagic infarction by Cilostazol in experimental ischemia-reperfusion mice (2011)
  • Author(s): Kasahara Y, Matsuyama T, Nagatsuka K, Taguchi A.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Glucocorticoid-induced TNF receptor-stimulated T cells serve as a negative regulator for CNS repair after cerebral infarction (2011)
  • Author(s): Takata M, Nakagomi T, Kashiwamura S, Nakano-Doi A, Saino O, Okamura H, Mimura O, Soma T, Taguchi A, Matsuyama T.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Expression of neural stem cells induced by transient cortical ischemia in mice (2011)
  • Author(s): Momota Y, Nakagomi T, Nakano-Doi A, Saino O, Y, Taguchi A, Takata M, Tsukamoto Y, Miyamae M, Kotani J, Matsuyama T.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Edaravone is effective to ameliorate the sensory neurologic deficit developed in chronic phase of cerebral infarction in mice (2011)
  • Author(s): Matsuyama T, Doe N, Nakagomi T, Nakano-Doi A, Saino O, Takata M, Lu S, Mimura O, Tachibana H, Taguchi A.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Effect of Soluble Cilostazol on Cerebral Blood Flow after Acute Ischemic Stroke in Mice (2011)
  • Author(s): Lu S, Nakagomi T, Nakano-Doi A, Takata M, Okamoto N, Mimura O, Ito Y, Taguchi A, Tachibana H, Matsuyama T.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Ischemia-induced neural stem/progenitor cells express pyramidal cell-markers in vivo and in vitro (2011)
  • Author(s): Clausen M, Nakano-Doi A, Saino O, Takata M, Nakagomi T, Luiten P, Matsuyama T.
  • Organizer: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function & Xth International Conference on Quantification of Brain Function and PET, Brain 2011
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110524-28
• [Presentation] Glucocorticoid-induced TNF receptor(GITR)刺激が脳梗塞後の神経再生に及ぼす影響 (2010)
  • Author(s): 田片将士, 中込隆之, 柏村信一郎, 斉野織恵, 土居亜紀子, 盧山, 田口明彦, 笠原由紀子, 三村治, 松山知弘
  • Organizer: 第22回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20101126-27
• [Presentation] マウス虚血再灌流モデルにおける神経幹細胞発現の検討 (2010)
  • Author(s): 百田義弘, 中込隆之, 中野亜紀子, 沖中由佳, 斉野織恵, 笠原由紀子, 田口明彦, 田片将士, 盧山, 百田義弘, 宮前雅見, 小谷順一郎, 松山知弘
  • Organizer: 第22回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20101126-27
• [Presentation] 可溶化シロスタゾール脳梗塞急性期投与の脳血流に及ぼす影響の検討 (2010)
  • Author(s): 盧山, 土居亜紀子, 中込隆之, 田片将士, 斉野織恵, 岡本紀夫, 田口明彦, 立花久大, 松山知弘
  • Organizer: 第22回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20101126-27
• [Presentation] A simple and highly reproducible model of permanent cerebral ischemia in CB-17 and SCID mice (2010)
  • Author(s): Taguchi A, Kasahara Y, Hirose H, Saino O, Takata M, Nakagomi T, Matsuyama T, Fukunaga M, Ishikawa, M.
  • Organizer: World Stroke Congress
  • Place of Presentation: Soeal, Korea
  • Year and Date: 20101113-16
• [Presentation] GITR(Glucocorticoid-induced TNF receptor) triggering reduces, and its inhibition enhances, endogenous neurogenesis in post-stroke brain (2010)
  • Author(s): Takata M, Kashiwamura S, Nakagomi T, Saino O, Nakano-Doi A, Doe N, Nakagomi N, Okamura H, Mimura O, Taguchi A, Matsuyama T.
  • Organizer: World Stroke Congress
  • Place of Presentation: Soeal, Korea
  • Year and Date: 20101013-16
• [Presentation] CD25-positive T lymphocytes are key immunemodulators of neurogenesis after stroke (2010)
  • Author(s): Matsuyama T, Saino O, Nakagomi1 T, Nakano-Doi1 A, Takata M, Kashiwamura S, Doe N, Nakagomi N, Mimura O, Taguchi A.
  • Organizer: World Stroke Congress
  • Place of Presentation: Soeal, Korea
  • Year and Date: 20101013-16
• [Presentation] Telmisartan suppresses cerebral reperfusion injury through activation of eNOS and ERK1/2 in endothelial cells (2010)
  • Author(s): Kasahara Y, Taguchi A, Hirose H, Nakano-Doi A, Nakagomi T, Matsuyama T.
  • Organizer: 7th World Stroke Congress
  • Place of Presentation: Soeal, Korea
  • Year and Date: 20101013-16
• [Presentation] GITR(Glucocorticoid-induced TNF receptor)-positive T lymphocytes regulate endogenous neurogenesis in post-stroke brain (2010)
  • Author(s): Takata M, Kashiwamura S, Nakagomi T, Saino O, Nakano-Doi A, Doe N, Nakagomi N, Okamura H, Mimura O, Taguchi A, Matsuyama T.
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 20100902-04
• [Presentation] Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction, Neuro2010 (2010)
  • Author(s): Nakano-Doi A, Nakagomi T, Nakagomi N, Saino O, Takata M, Lu S, Tachibana H, Taguchi A, Matsuyama T.
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 20100902-04
• [Presentation] Depletion of CD4-positive T-lymphocytes Enhances Post-stroke Endogenous Neurogenesis, Neuro2010 (2010)
  • Author(s): Saino O, Taguchi A, Nakagomi1 T, Nakano-Doi1 A, Takata M, Kashiwamura S, Doe N, Matsuyama T.
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 20100902-04
• [Presentation] Effect of soluble cilostazol on cerebral blood flow after acute ischemic stroke in mice, Neuro2010 (2010)
  • Author(s): Lu S, Nakagomi T, Nakano-Doi A, Takata M, Okamoto N, Mimura O, Ito Y, Taguchi A, Tachibana H, Matsuyama T.
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 20100902-04
• [Presentation] T細胞除去が脳梗塞後の組織修復と機能回復に与える影響の検討 (2009)
  • Author(s): 斉野織恵, 中込隆之, 土居亜紀子, 土江伸誉, 中込奈美, 松山知弘, 柏村信一郎, 廣瀬遥香, 田口明彦
  • Organizer: 第21回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20091119-20
• [Presentation] 骨髄単核球投与が脳梗塞後の脳血管内皮細胞と神経幹細胞に及ぼす影響の検討 (2009)
  • Author(s): 中野亜紀子, 中込隆之, 藤川昌敏, 盧山, 斉野織恵, 田片将士, 中込奈美, 松山知弘, 田浦映恵, 田口明彦
  • Organizer: 第21回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20091119-20
• [Presentation] 実験的脳梗塞モデルにおける免疫動態の検討 (2009)
  • Author(s): 田片将士, 柏村信一郎, 中込隆之, 斉野織恵, 中野亜紀子, 盧山, 中込奈美, 田口明彦, 笠原由紀子, 三村治, 松山知弘
  • Organizer: 第21回日本脳循環代謝学会総会
  • Place of Presentation: 豊中
  • Year and Date: 20091119-20
• [Book] Ischemia-induced neural stem/progenitor cells within the post-stroke cortex in adult brains. Neural Stem Cells and Therapy, Chapter 16 (2012)
  • Author(s): Nakagomi T, Matsuyama T. Tao Sun
  • Total Pages: 978-953-307-958-5
  • Publisher: InTech-Open Access Publisher
• [Book] Neurogenesis in the cerberal cortex after stroke. M. A. Hayat(ed.), Stem Cells and Cancer Stem Cells, Volume 2 (2011)
  • Author(s): Kasahara Y, Nakagomi T, Matsuyama T, Taguchi A.
  • Publisher: Springer
• [Book] The therapeutic potential of neural stem cells in cerebral ischemia. Current Signal Transduction Therapy (2011)
  • Author(s): Kasahara Y, Nakagomi T, Nakano-Doi A, Matsuyama T, Taguchi A.
  • Total Pages: 6
• [Book] レビュー:神経再生療法-総合診療マニュアル(上原譽志夫,大林完二,隅谷護人,益子邦洋,松岡博昭,編集) (2010)
  • Author(s): 松山知弘
  • Total Pages: 277-279
  • Publisher: 金芳堂
• [Book] アポトーシス-特集:脳組織虚血性傷害のメカニズム-最新情報と臨床へのトランスレーション- BRAIN MEDICAL (2010)
  • Author(s): 松山知弘
  • Total Pages: 63-68
  • Publisher: メディカルレビュー社
• [Patent(Industrial Property Rights)] 脳梗塞後運動機能障害モデル動物及びその使用並びに運動機能回復に対する新規治療法の有効性のスクリーニング方法 (2012)
  • Inventor(s): 田口明彦、笠原由紀子、松山知弘
  • Industrial Property Rights Holder: 財団法人先端医療振興財団
  • Industrial Property Number: 特願、2012-040102
  • Filing Date: 2012-02-27
• [Patent(Industrial Property Rights)] 脳梗塞後うつ病モデル動物及びその使用並びにうつ状態に対する被検薬物及び移植細胞の有効性のスクリーニング方法 (2012)
  • Inventor(s): 松山知弘、土江伸誉、田口明彦
  • Industrial Property Rights Holder: 財団法人先端医療振興財団
  • Industrial Property Number: 特願、2012-053456
  • Filing Date: 2012-03-09
• [Patent(Industrial Property Rights)] 神経幹細胞の調製法 (2012)
  • Inventor(s): 松山知弘、田口明彦、芳川浩男
  • Industrial Property Rights Holder: 公益財団法人新産業創造研究機構
  • Industrial Property Number: 特許、特許第4905719号
  • Acquisition Date: 2012-01-20