Analysis of bone marrow-derived progenitor pericytes and their therapeutic application for cerebral infarction

• Project/Area Number: 15K09329
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• 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): 藤盛 好啓 兵庫医科大学, 医学部, 教授 (20229058) ; 中込 隆之 兵庫医科大学, 医学部, 准教授 (80434950)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ペリサイト / 造血幹細胞 / 細胞治療 / 脳梗塞 / 血液脳関門

Outline of Final Research Achievements

Stem cell-based regenerative medicine has been well documented to improve the neurological outcome of post-stroke patients. We recently have found a new candidate of stem cells from the post-infarct bone marrow (BM), which can differentiate into pericytes forming neurovascular unit in the brain. The current study was performed to analyze the BM-derived progenitor pericytes (PPCs) and their therapeutic application for cerebral infarction was noted. FACS analysis revealed that the PPCs were divided into two subclasses, CD45high/CD44(+) and CD45low/CD44(-), both of which differentiated into blood cells and vascular cells showing capillary formation under specific culture medium. However, the latter showed the tube formation, the primitive vascular lumen. These findings suggest that CD45low/CD44(-) subclass are hemangioblast-like cells differentiating into both endothelial and pericytes, which may accomplish therapeutic angiogenesis for stroke.

Research Products

• [Journal Article] lschemic stroke activates the VE-cadherin prometer and increases VE-cadherin expression in adult mice (2018)
  • Author(s): Nakano-Doi A, Sakuma R, Matsuyama T, Nakagomi T
  • Journal Title: Histlogy and Histpathology Volume: 33 Pages: 507-521
  • Peer Reviewed / Open Access
• [Journal Article] Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion (2017)
  • Author(s): Uemura Maiko T.、Ihara Masafumi、Maki Takakuni、Nakagomi Takayuki、Kaji Seiji、Uemura Kengo、Matsuyama Tomohiro、Kalaria Raj N.、Kinoshita Ayae、Takahashi Ryosuke
  • Journal Title: Brain Pathology Volume: 31 May Issue: 4 Pages: 1-15
  • DOI: 10.1111/bpa.12523
  • NAID: 120006305874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of multipotent stem cells in human brain tissue following stroke (2017)
  • Author(s): Kotaro Tatebayashi, Yasue Tanaka, Akiko Nakano-Doi, Rika Sak Saeko Kamachi, Manabu Shirakawa, Kazutaka Uchida, Hiroto Kageyamauma,, Toshinori Takagi, Shinichi Yoshimura, Tomohiro Matsuyama, Takayuki Nakagomi
  • Journal Title: Stem Cells Development Volume: 未定 Issue: 11 Pages: 787-797
  • DOI: 10.1089/scd.2016.0334
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Induction of Perivascular Neural Stem Cells and Possible Contribution to Neurogenesis Following Traansient Brain Ischemia/Reperfusion Injury (2017)
  • Author(s): Masayo Nakata, Takayuki Nakagomi, Mitsuyo Maeda, Akiko Nakano-Doi, Yoshihiro Momota, Tomohiro Matsuyama
  • Journal Title: Transl. Stroke Res. Volume: 8 Issue: 2 Pages: 131-143
  • DOI: 10.1007/s12975-016-0479-1
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Expression patterns and phenotypic changes regarding stemness in brain pericytes in health and disease, (2016)
  • Author(s): Nakano-Doi A, Nakagomi T, Sakuma R, Takahashi A, Tanaka Y, Kawamura M, Matsuyama T.
  • Journal Title: Journal of stem cell research & therapy Volume: 6 Pages: 1000332-1000332
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model. (2016)
  • Author(s): Kasahara Y, Yamahara K, Soma T, Stern DM, Nakagomi T, Matsuyama T, Taguchi A.
  • Journal Title: Transl Res. Volume: 176 Pages: 69-80
  • DOI: 10.1016/j.trsl.2016.04.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Absence of Sema4D improves oligodendrocyte recovery after cerebral ischemia/reperfusion injury in mice. (2016)
  • Author(s): Wada T, Sawano T, Tanaka T, Furuyama T, Fukumoto M, Yamaguchi W, Saino O, Takeda Y, Kogo M, Matsuyama T, Inagaki S.
  • Journal Title: Neurosci Res. Volume: 108 Pages: 6-11
  • DOI: 10.1016/j.neures.2015.12.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. (2016)
  • Author(s): Sakuma R, Kawahara M, Nakano-Doi A, Takahashi A, Tanaka Y, Narita A, Kuwahara-Otani S, Hayakawa T, Yagi H, Matsuyama T, Nakagomi T.
  • Journal Title: J Neuroinflammation. Volume: 13(1)57 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s12974-016-0523-9
  • Peer Reviewed / Open Access
• [Journal Article] Brain Vascular Pericytes Following Ischemia Have Multipotential Stem Cell Activity to Differentiate into Neural and Vascular Lineage Cells. (2015)
  • Author(s): Nakagomi T, Kubo S, Nakano-Doi A, Sakuma R, Lu S, Narita A, Kawahara M, Taguchi A, Matsuyama T.
  • Journal Title: Stem Cells. Volume: ー Issue: 6 Pages: 1962-1974
  • DOI: 10.1002/stem.1977
  • Peer Reviewed / Open Access
• [Journal Article] Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients (2015)
  • Author(s): Taguchi A, Sakai C, Soma T, Kasahara Y, Stern D, Kajimoto K, Ihara M, Daimon T, Yamahara K, Doi K, Kohara N, Nishimura H, Matsuyama T, Naritomi H, Sakai N, Nagatsuka K
  • Journal Title: Stem Cells Dev Volume: 24 Issue: 19 Pages: 2207-18
  • DOI: 10.1089/scd.2015.0160
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脳梗塞巣におけるLPGDSの発現 (2018)
  • Author(s): 宮谷尚伽, 百田義弘, 蒲池紗英子, 土居亜紀子, 中込隆之, 松山知弘.
  • Organizer: 第43回日本脳卒中学会学術集会 (STROKE 2018)
• [Presentation] ヒト脳傷害誘導性多能性幹細胞の性状とその特徴 (2018)
  • Author(s): 髙木俊範, 立林洸太朗, 別府幹也, 蔵本要二, 土居亜紀子, 佐久間理香，中込隆之, 松山知弘, 吉村紳一
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] Ischemia-induced multipotent stem cells in human cerebral infarction (2018)
  • Author(s): Tatebayashi K, Takagi T, Nakano-Doi A, Sakuma R, Tanaka Y, Kamachi S, Shirakawa M, Uchida K, Kageyama H, Nakagomi T, Matsuyama T, Yoshimura S
  • Organizer: International Stroke Conference 2018
  • Int'l Joint Research
• [Presentation] 脳卒中の幹細胞治療 (2018)
  • Author(s): 松山知弘
  • Organizer: 第22回口腔顔面神経機能学会
  • Invited
• [Presentation] Pericyte と脳梗塞治療 (2018)
  • Author(s): 松山知弘, 中込隆之
  • Organizer: 第43回日本脳卒中学会学術集会 (STROKE 2018)
  • Invited
• [Presentation] Brain endogenous multipotent stem cells following ischemia express CD44 and differentiate into oligodendrocytes (2017)
  • Author(s): 澤田里佳子, 佐久間理香, 土居亜紀子, 高橋愛, 蒲池紗英子, 中込隆之, 松山知弘
  • Organizer: 第40回神経科学大会
• [Presentation] Analysis of the characterization of ischemic pericyte. (2017)
  • Author(s): 湊雄介, 高橋愛, 加藤歩, 大谷佐知, 田中宏一, 前田誠司, 中込隆之, 松山知弘, 八木秀司
  • Organizer: 第40回神経科学大会
• [Presentation] 発生期及び梗塞脳におけるVE-cadherinの発現に関する検討 (2017)
  • Author(s): 中込隆之, 土居亜紀子, 佐久間里香, 松山知弘
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Presentation] ヒト脳梗塞組織における多能性幹細胞の同定 (2017)
  • Author(s): 立林洸太朗，高木俊範，土居亜紀子，佐久間理香，田中康江，白川 学，陰山博人，内田和孝，蒲池紗英子，中込隆之，松山知弘，吉村紳一
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Presentation] 脳梗塞後のCD44の局在と傷害誘導性多能性幹細胞の神経系への分化 (2017)
  • Author(s): 澤田里佳子, 佐久間理香, 土居亜紀子, 高橋 愛, 蒲池紗英子, 中込隆之, 松山知弘
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Presentation] ヒト脳梗塞巣における脳傷害誘導性幹細胞の確立 (2017)
  • Author(s): 髙木俊範, 立林洸太朗, 別府幹也, 蔵本要二, 中込隆之, 松山知弘, 吉村紳一
  • Organizer: 第18回日本分子脳神経外科学会,
• [Presentation] ペリサイトの起源と脳組織再生への関与 (2017)
  • Author(s): 松山知弘，中込隆之
  • Organizer: 第60回日本脳循環代謝学会学術集会
  • Invited
• [Presentation] 脳ペリサイト由来多能性幹細胞、間葉系幹細胞、脂肪組織由来幹細胞の特性に関する比較検討 (2016)
  • Author(s): 高橋 愛, 中込 隆之, 土居 亜紀子, 佐久間 理香, 澤田 里佳子, 松山 知弘
  • Organizer: 第59回日本脳循環代謝学会学術集会
  • Place of Presentation: 徳島県徳島市あわぎんホール
  • Year and Date: 2016-11-11
• [Presentation] 脱分化脂肪細胞の神経系分化とマウス脳梗塞モデルへの細胞移植による脳分布 (2016)
  • Author(s): 覚道 知樹, 岸本 直隆, 土居 亜紀子, 中込 隆之, 百田 義弘, 松山 知弘
  • Organizer: 第59回日本脳循環代謝学会学術集会
  • Place of Presentation: 徳島県徳島市あわぎんホール
  • Year and Date: 2016-11-11
• [Presentation] 虚血ペリサイトの発生学的見地から見た特性の検討, シンポジウム3「再生医療の基礎と臨床UP to DATE」． (2016)
  • Author(s): 土居 亜紀子, 中込 隆之, 佐久間 理香, 高橋 愛, 田中 康恵, 川村 美貴,松山 知弘
  • Organizer: 第59回日本脳循環代謝学会学術集会
  • Place of Presentation: 徳島県徳島市あわぎんホール
  • Year and Date: 2016-11-11
  • Invited
• [Presentation] 神経再生療法は脳虚血再灌流病態時でも可能か (2016)
  • Author(s): 中田 雅代, 中込 隆之, 前田 光代, 土居 亜紀子, 百田 義弘, 松山 知弘
  • Organizer: 第59回日本脳循環代謝学会学術集会
  • Place of Presentation: 徳島県徳島市あわぎんホール
  • Year and Date: 2016-11-11
• [Presentation] PDGFRβ-expressing brain pericytes following ischemia acquire microglia-generating multipotent stem cell activity. (2016)
  • Author(s): Rika Sakuma, Maiko Kawahara, Akiko Doi, Ai Takahashi, Yasue Tanaka, Aya Narita, Sachi Otani, Tetsu Hayakawa, Hideshi Yagi, Tomohiro Matsuyama, Takayuki Nakagomi
  • Organizer: The 39th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 神奈川県横浜市パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] BMP-4 expression by pericytes after chronic ischemia aggravates white matter damage. (2016)
  • Author(s): Maiko Uemura, Masafumi Ihara, Takayuki Nakagomi, Takakuni Maki, Seiji Kaji, Kengo Uemura, Kazuyuki Nagatsuka, Tomohiro Matsuyama, Raj Kalaria, Ayae Kinoshita, Ryosuke Takahashi
  • Organizer: The 39th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 神奈川県横浜市パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] 内在性神経幹細胞による脳梗塞の再生治療, シンポジウム．セッションタイトル：脳梗塞の創薬と次世代医療 (2016)
  • Author(s): 松山 知弘,中込 隆之
  • Organizer: 第57回神経学会学術大会
  • Place of Presentation: 兵庫県神戸市神戸コンベンションホー
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] BMP-4 expression by pericytes after ischemia aggravates white matter damage. (2016)
  • Author(s): 上村 麻衣子, 猪原 匡史,中込 隆之, 眞木 崇州, 梶 誠兒, 植村 健吾, 長束 一行,松山 知弘, Kalaria Raj, 木下 彩栄, 高橋 良輔,
  • Organizer: 第57回神経学会学術大会
  • Place of Presentation: 兵庫県神戸市神戸コンベンションホール
  • Year and Date: 2016-05-18
• [Presentation] Brain pericytes following ischemia acquire neural phenotypes in a mesenchymal-epithelial transition like manner (2015)
  • Author(s): Takayuki Nakagomi, Akiko Doi,Rika Sakuma, Aya Narita, Yasue Tanaka, Masayo Nakata, <U>Shuji Kubo, Tomohiro Matsuyama
  • Organizer: The 38th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 神戸コンベンションセンター（兵庫県、神戸市）
  • Year and Date: 2015-07-28
• [Presentation] 脳梗塞後の内在性神経幹細胞の動態 (2015)
  • Author(s): 松山 知弘,中込 隆之
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県、新潟市）
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] Brain Vascular Pericytes Acquire Stemness Following Ischemic Insult (2015)
  • Author(s): Tomohiro Matsuyama, Shuji Kubo, Akiko Nakano-Doi, Rika Sakuma, Shan Lu, Aya Narita, Maiko Kawahara, Miki Kawamura, Akihiko Taguchi, Takayuki Nakagomi
  • Organizer: The European Stroke Organisation Conference 2015
  • Place of Presentation: grasgow, UK
  • Year and Date: 2015-04-17
  • Int'l Joint Research