Repairing mechanism of human mesenchymal stem cells (hMSCs) via immune regulation on ischemia brain injury

• Project/Area Number: 25462236
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Showa University
• Principal Investigator: OHTAKI HIROKAZU 昭和大学, 医学部, 講師 (20349062)
• Co-Investigator(Renkei-kenkyūsha): SHIODA SEIJI 星薬科大学, 先端生命科学研究所, 特任教授 (80102375) ; Rakwal Randeep 筑波大学, 生命科学研究科, 教授 (70590850) ; MIYAZAKI TAKURO 昭和大学, 医学部, 講師 (80398693)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 骨髄間葉系幹細胞 / 脳虚血 / マイクログリア / マイクロアレイ / 神経細胞死 / 移植細胞治療 / 炎症性サイトカイン

Outline of Final Research Achievements

Human bone marrow derived mesenchymal stem cells (hMSCs) attract the attention of tissue repair during several diseases. The purpose of the preset study is to determine the mechanism of hMSCs on tissue repair. In particular, we focused on the relationship between hMSCs and macrophages and microglia. hMSCs suppressed inducible nitric oxide synthase (iNOS) and NO production from BV-2 microglia after interferon-γ stimulation in the cell number dependent fashion. Moreover, by the transcriptome analysis, hMSCs cultured with ischemic hippocampal homogenate increased 98 transcriptomes including chemokines. Further analysis was determined a chemokine, CCL2 from hMSCs was regulated by inflammatory cytokines induced by ischemic stress.

Research Products

• [Journal Article] Therapeutic effects and mechanism of conditioned media from human mesenchymal stem cells on anti-GBM glomerulonephritis in WKY rats. (2016)
  • Author(s): Iseri K, Iyoda M, Ohtaki H, Matsumoto K, Wada Y, Suzuki T, Yamamoto Y, Saito T, Hihara K, Tachibana S, Honda K, Shibata T.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 10 Issue: 11 Pages: 1152-1152
  • DOI: 10.1152/ajprenal.00165.2016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP-specific receptor. (2016)
  • Author(s): Xu Z, Ohtaki H, Watanabe J, Miyamoto K, Murai N, Sasaki S, Matsumoto M, Hashimoto H, Hiraizumi Y, Numazawa S, Shioda S.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22373-22373
  • DOI: 10.1038/srep22373
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. (2016)
  • Author(s): Matsumoto M, Nakamachi T, Watanabe J, Sugiyama K, Ohtaki H, Murai N, Sasaki S, Xu Z, Hashimoto H, Seki T, Miyazaki A, Shioda S.
  • Journal Title: J Mol Neurosci Volume: 10 Issue: 2 Pages: 1007-1007
  • DOI: 10.1007/s12031-016-0731-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PACAP38 suppresses cortical damage in mice with traumatic brain injury by enhancing antioxidant activity. (2014)
  • Author(s): Miyamoto K, Tsumuraya T, Ohtaki H, Dohi K, Satoh K, Xu Z, Tanaka S, Murai N, Watanabe J, Sugiyama K, Aruga T, Shioda S
  • Journal Title: J Mol Neurosci Volume: in press
  • Peer Reviewed
• [Journal Article] Establishment and Characterization of Primary Adult Microglial Culture in Mice (2013)
  • Author(s): Ohtaki H, Tsumuraya T, Song D, Sato A, Ohara K, Miyamoto K, Nakano H, Kiriyama K, Dohi K, Hiraizumi H, Matsunaga M, Shioda S
  • Journal Title: Acta Neurochir Suppl Volume: 118 Pages: 49-54
  • DOI: 10.1007/978-3-7091-1434-6_8
  • ISBN: 9783709114339, 9783709114346
  • Peer Reviewed
• [Journal Article] Therapeutic effects of human mesenchymal stem cells in wistar-kyoto rats with anti-glomerular basement membrane glomerulonephritis. (2013)
  • Author(s): Suzuki T, Iyoda M, Shibata T, Ohtaki H, Matsumoto K, Shindo-Hirai Y, Kuno Y, Wada Y, Yamamoto Y, Kawaguchi M, Shioda S, Akizawa T.
  • Journal Title: PLoS One Volume: 24 Issue: 6 Pages: e67475-e67475
  • DOI: 10.1371/journal.pone.0067475
  • Peer Reviewed
• [Journal Article] PACAP Attenuates NMDA-Induced Retinal Damage in Association with Modulation of the Microglia/Macrophage Status into an Acquired Deactivation Subtype. (2013)
  • Author(s): Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Tsuchida M, Yoshikawa A, Matkovits A, Kagami N, Imai N, Fujisaka S, Usui I, Tobe K, Koide R, Takahashi H, Shioda S
  • Journal Title: J Mol Neurosci. Volume: 51(2) Issue: 2 Pages: 493-502
  • DOI: 10.1007/s12031-013-0017-5
  • Peer Reviewed
• [Journal Article] Activation of microglia induces symptoms of Parkinson's disease in wild-type, but not in IL-1 knockout mice. (2013)
  • Author(s): Tanaka S, Ishii A, Ohtaki H, Shioda S, Yoshida T, Numazawa S.
  • Journal Title: J Neuroinflammation. Volume: 10 Issue: 1 Pages: 143-143
  • DOI: 10.1186/1742-2094-10-143
  • Peer Reviewed
• [Journal Article] Low dose of methylmercury (MeHg) exposure induces caspase mediated-apoptosis in cultured neural progenitor cells. (2013)
  • Author(s): Watanabe J, Nakamachi T, Ohtaki H, Naganuma A, Shioda S, Nakajo S.
  • Journal Title: J Toxicol Sci. Volume: 38 Pages: 931-935
  • NAID: 130004447097
  • Peer Reviewed
• [Journal Article] Status of Systemic Oxidative Stress during Therapeutic Hypothermia in Patients with Post-Cardiac Arrest Syndrome. (2013)
  • Author(s): Dohi K, Miyamoto K, Fukuda K, Nakamura S, Hayashi M, Ohtaki H, Shioda S, Aruga T
  • Journal Title: Oxid Med Cell Longev. Volume: 2013 Pages: 562429-562429
  • DOI: 10.1155/2013/562429
  • Peer Reviewed
• [Journal Article] The anti-inflammatory property of human bone marrow-derived mesenchymal stem/stromal cells is preserved in late-passage cultures. (2013)
  • Author(s): Song D, Ohtaki H, Tsumuraya T, Miyamoto K, Shibato J, Rakwal R, Xu Z, Hiraizumi Y, Inoue T, Shioda S
  • Journal Title: J Neuroimmunol. Volume: 263(1-2) Issue: 1-2 Pages: 55-63
  • DOI: 10.1016/j.jneuroim.2013.07.018
  • Peer Reviewed
• [Journal Article] Edaravone Increases Regional Cerebral Blood Flow After Traumatic Brain Injury in Mice (2013)
  • Author(s): Miyamoto K, Ohtaki H, Dohi K, Tsumuraya T, Nakano H, Kiriyama K, Song D, Aruga T, Shioda S
  • Journal Title: Acta Neurochir Suppl Volume: 118 Pages: 103-9
  • DOI: 10.1007/978-3-7091-1434-6_18
  • ISBN: 9783709114339, 9783709114346
  • Peer Reviewed
• [Journal Article] Therapeutic time window for edaravone treatment of traumatic brain injury in mice. (2013)
  • Author(s): Miyamoto K, Ohtaki H, Dohi K, Tsumuraya T, Song D, Kiriyama K, Satoh K, Shimizu A, Aruga T, Shioda S
  • Journal Title: Biomed Res Int. Volume: 2013 Pages: 379206-379206
  • DOI: 10.1155/2013/379206
  • Peer Reviewed
• [Presentation] エクリン汗腺におけるPACAPの汗分泌促進作用 (2016)
  • Author(s): 渡邊 潤, 佐々木 駿, 中町 智哉, 大滝 博和, 荒田 悟, 本田 一穂, 塩田 清二
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 未来科学館，東京
  • Year and Date: 2016-05-13
• [Presentation] 脳虚血ホモジネート刺激によるヒト骨髄間葉系幹・前駆細胞（hMSCs）のCCL2産生機構の解明 (2016)
  • Author(s): 大滝博和、渡邊潤、谷口紗季、本田一穂
  • Organizer: 第１２１回日本解剖学会総会・全国学術集会
  • Place of Presentation: ビックパレットふくしま，郡山
  • Year and Date: 2016-03-28
• [Presentation] エクリン汗腺におけるPACAPの汗分泌促進作用 (2016)
  • Author(s): 渡邊 潤, 佐々木 駿, 中町 智哉, 大滝 博和, 荒田 悟, 本田 一穂, 塩田 清二
  • Organizer: 第１２１回日本解剖学会総会・全国学術集会
  • Place of Presentation: ビックパレットふくしま，郡山
  • Year and Date: 2016-03-28
• [Presentation] Crucial role of PACAP in neural progenitor cells during development and after degeneration. (2015)
  • Author(s): Watanabe J, Ohtaki H, Nakamachi T, Matsumoto M, Sasaki S, Murai M, Arata S, Shioda S.
  • Organizer: Neuropeptides 2015
  • Place of Presentation: Aberdeen, UK
  • Year and Date: 2015-09-28
  • Int'l Joint Research
• [Presentation] Effects of PACAP on the secretions of tear and saliva in mouse. (2015)
  • Author(s): Nakamachi T, Watanabe J, Seki T, Ohtaki H, Shioda S
  • Organizer: Neuropeptides 2015
  • Place of Presentation: Aberdeen, UK
  • Year and Date: 2015-09-28
  • Int'l Joint Research
• [Presentation] PACAP contributes to proliferation of hematopoietic stem/progenitor cells in murine bone marrow. (2015)
  • Author(s): Ohtaki H, Xu Z, Watanabe J, Hiraizumi Y, Hashimoto H, Numazawa S, Shioda S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: Cappadocia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] ACAP contributes proliferation of hippocampal neural stem/progenitor cells after global ischemi in mice (2015)
  • Author(s): Nakamachi T, Ohtaki H, Watanabe J, Shioda S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: Cappadocia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] Involvement of PACAP in differentiation of neural progenitor cells via radial glia (2015)
  • Author(s): Watanabe J, Ohtaki H, Nakamachi T, Sasaki S, Matsumoto M, Murai N, Seki T, Arata S, Shioda S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: Cappadocia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] Expression and localization of PACAP specific receptor (PAC1R) in the mouse bone marrow. (2015)
  • Author(s): 徐枝芳，大滝博和，渡邊潤，平泉裕，沼澤聡，塩田清二
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム，東京
  • Year and Date: 2015-07-21
• [Presentation] ヒト骨髄間葉系幹細胞はPACAPを介して脊髄損傷後の炎症を調節する。 (2015)
  • Author(s): 大滝博和, 圓谷智海, 徐枝芳, 渡邊潤, 佐藤敦, 平泉裕, 橋本均, 塩田清二
  • Organizer: 第８０回日本インターフェロン・サイトカイン学会大会
  • Place of Presentation: 東京工業大学，東京
  • Year and Date: 2015-07-17
• [Presentation] 糖尿病モデルマウスに対する骨髄由来ヒト間葉系幹細胞(hMSCs)の膵臓内投与における有用性の検討 (2015)
  • Author(s): 村井謙允，大滝博和，渡邊潤，佐々木駿，松本皆子，泉崎雅彦
  • Organizer: 第320回昭和大学学士会例会
  • Place of Presentation: 昭和大学，東京
  • Year and Date: 2015-05-27
• [Presentation] 腺におけるPituitary Adenylate Cyclase Activating Polypeptide （PACAP）の汗分泌促進効果 (2015)
  • Author(s): 佐々木駿，渡邊潤，大滝博和，松本皆子，村井謙允，宮崎章
  • Organizer: 第320回昭和大学学士会例会
  • Place of Presentation: 昭和大学，東京
  • Year and Date: 2015-05-27
• [Presentation] Pituitary adenylate cyclase activating polypeptide (PACAP)の成体海馬神経新生・再生への関与について (2015)
  • Author(s): 松本皆子，渡邊潤，村井謙允，佐々木，大滝博和，宮崎章
  • Organizer: 第320回昭和大学学士会例会
  • Place of Presentation: 昭和大学，東京
  • Year and Date: 2015-05-27
• [Presentation] PACAP contributes to the proliferation of hematopoietic stem/progenitor cells in murine bone marrow via its specific receptor PAC1. (2015)
  • Author(s): Xu Z, Ohtaki H, Watanabe J, Nakamachi T, Numazawa S, Shioda S.
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 未来科学館，東京
  • Year and Date: 2015-05-15
• [Presentation] 神経前駆細胞に対するグレリンの作用の解析 (2015)
  • Author(s): 渡邊潤, 影山晴秋, 大滝博和, 松本皆子, 佐々木駿, 村井謙允, 荒田悟, 塩田清二
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 未来科学館，東京
  • Year and Date: 2015-05-15
• [Presentation] PACAPの抗酸化誘導作用と加齢性神経変性との関連 (2014)
  • Author(s): 中町智哉，大滝博和，渡邊潤，吉川輝，土田将史，杉山公一，加賀美信幸，今井ノリ，塩田清二
  • Organizer: 第１１９回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・下野
• [Presentation] Expression of PACAP/VIP and their receptors in the mouse bone marrow (2014)
  • Author(s): 徐枝芳，大滝博和，中町智哉，渡邊潤，宋丹丹，宮本和幸，平泉裕，沼澤聡，塩田清二
  • Organizer: 第１１９回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・下野
• [Presentation] 脳虚血刺激によるヒト骨髄間葉系幹細胞の応答 (2014)
  • Author(s): 大滝博和，谷口紗季，徐枝芳，渡邊潤，宋丹丹，宮本和幸，塩田 清二
  • Organizer: 第１１９回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・下野
• [Presentation] 頭部外傷モデルマウスにおけるMRIを用いた神経障害の解析 (2014)
  • Author(s): 渡邊潤，大滝博和，Darwin J Prockop, 塩田清二
  • Organizer: 第１１９回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・下野
• [Presentation] マウス頭部外傷におけるPACAPの神経保護作用についての検討 (2014)
  • Author(s): 宮本和幸，大滝博和，土肥謙二，佐藤和恵，宋丹丹，徐枝芳，村井謙充，渡邉潤，田中佐知子，有賀徹，塩田清二
  • Organizer: 第１１９回日本解剖学会総会・全国学術集会
  • Place of Presentation: 栃木・下野
• [Presentation] Expression and localization of PACAP specific receptor PAC1R in mouse bone marrow (2014)
  • Author(s): 徐 枝芳、大滝 博和、渡邊 潤、宮本 和幸、村井謙允、中町 智哉、平泉 裕、沼澤 聡、塩田 清二
  • Organizer: 第11回GPCR研究会
  • Place of Presentation: 東京
• [Presentation] Expression and localization of PACAP specific receptor (PAC1R) in bone marrow of mice (2014)
  • Author(s): 徐 枝芳、大滝 博和、渡邊 潤、宮本 和幸、村井謙允、中町 智哉、平泉 裕、沼澤 聡、塩田 清二
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄
• [Presentation] 脊髄損傷マウスにおけるマイクログリア／マクロファージ活性化へのインターロイキン１の関与 (2013)
  • Author(s): 佐藤敦，大滝博和，小原賢司，圓谷智海，平泉裕，渥美敬，塩田清二
  • Organizer: 第86回日本整形外科学会学術総会
  • Place of Presentation: 広島，広島
• [Presentation] Effect of water intake on heatstroke of mice. (2013)
  • Author(s): Miyamoto K, Ohtaki H, Miyake Y, Shioda S, Aruga T
  • Organizer: 7th Asian Conference on Emergency Medicine (ACEM)
  • Place of Presentation: Tokyo, Japan
• [Presentation] Human bone marrow-derived mesenchymal stem cells suppressed classical activation of microglial cells (2013)
  • Author(s): Ohtaki H, Song D, Xu Z, Miyamoto K, Shibato J, Rakwal R, Dohi K, Hiraizumi Y, Shioda S
  • Organizer: Neuroscience meeting SFN2013
  • Place of Presentation: San Diego, CA
• [Presentation] Human stem/progenitor cells from bone marrow improve spinal cord injury via communicating with PACAP. (2013)
  • Author(s): Ohtaki H, Tsumuraya T, Song D, Sato A, Xu Z, Miyamoto K, Hiraizumi Y, Nakamachi T, Hashimoto H, Shintani N, Shioda S
  • Organizer: The 11th International Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Pecs, Hungary
• [Presentation] PACAP stimulates the corneal healing via lacrimal-mediating and direct pathways in mouse. (2013)
  • Author(s): Nakamachi T, Seki T, Wada Y, Ohtaki H, Kagami N, Imai N, Arata S, Hashimoto H, Shintani N, Farkas J, Matkovits A, Reglodi D, Shioda S
  • Organizer: The 11th International Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Pecs, Hungary
• [Presentation] The anti-inflammatory property of human bone marrow-derived mesenchymal stem cells is preserved in late-passage cultures.
  • Author(s): Ohtaki H, Song D, Tsumuraya T, Miyamoto K, Shibato J, Rakwal R, Xu Z, Inoue T, Shioda S
  • Organizer: 6th International Symposium on mesenchymal stem/progenitor cells
  • Place of Presentation: College Station, TX
• [Presentation] Localization of pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (PAC1R) in bone marrow of mice
  • Author(s): 徐枝芳，大滝博和，中町智哉，渡邊潤，塩田清二
  • Organizer: 日本解剖学会関東支部第１０１回学術集会
  • Place of Presentation: 東京
• [Book] Pituitary Adenylate Cyclase Activating Polypeptide - PACAP, (Eds. Reglodi D and Tamas A) (2016)
  • Author(s): Ohtaki H and Shioda S.
  • Publisher: Springer Nature (New York)
• [Book] Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2016)
  • Author(s): Ohtaki H
  • Total Pages: 6
  • Publisher: Elsevier (USA)
• [Book] 最新臨床脳卒中学（上）７月号増刊 (2014)
  • Author(s): 大滝博和，渡邊潤，塩田清二
  • Total Pages: 3
  • Publisher: 日本臨床社
• [Book] Neuroanesthesia and Cerebro-Spinal Protection (Hiroyuki Uchino, Kazuo Ushijima, Yukiko Ikeda eds) (2014)
  • Author(s): Ohtaki H, Shioda S
  • Total Pages: 8
  • Publisher: Springer (Tokyo)