Analysis for therapeutic effects of mesenchymal stem/progenitor cells on neuropsychological disorder after traumatic brain injury.

• Project/Area Number: 25861289
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Showa University
• Principal Investigator: Watanabe Jun 昭和大学, 遺伝子組換え実験室, 助教 (50649069)
• Research Collaborator: SHIODA Seiji ; Ohtaki Hirokazu ; Darwin Prockop ; Ashok Shetty
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 頭部外傷 / 骨髄由来間葉系幹細胞 / 高次脳機能障害 / 血液脳関門 / アストロサイト / 高次脳機能要害 / 骨髄間葉系幹細胞 / TSG-6

Outline of Final Research Achievements

Traumatic brain injury (TBI) causes multiple long-term defects including a loss of working memory that is frequently incapacitating. Administrations of mesenchymal stem/stromal cells (MSCs) previously produced beneficial effects in models of TBI as well as other disease models. In several models, the beneficial effects were explained by the MSCs being activated to express TSG-6. In a mouse model of TBI, we found the intravenous human MSCs or TSG-6 decreased the blood brain barrier leakage. In this time, the expression of GFAP was significantly increased. Administration of TSG-6 also decreased the lesion size at 2 weeks. Importantly, the acute administration of TSG-6 within 24 h of TBI was followed 6 to 10 weeks later by improvements in memory, depressive-like behavior and the number of newly born-neurons. The data suggested that acute administration of TSG-6 may be an effective therapy for decreasing some of the long-term consequences of TBI.

Research Products

• [Journal Article] Pituitary adenylate cyclase-activating polypeptide promotes eccrine gland sweat secretion. (2017)
  • Author(s): Sasaki S, Watanabe J, Ohtaki H, Matsumoto M, Murai N, Nakamachi T, Hannibal J, Fahrenkrug J, Hashimoto H, Watanabe H, Sueki H, Honda K, Miyazaki A, Shioda S.
  • Journal Title: Br J Dermatol. Volume: 176 Issue: 2 Pages: 413-422
  • DOI: 10.1111/bjd.14885
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] Continuous intake of the Chaga mushroom (Inonotus obliquus) aqueous extract suppresses cancer progression and maintains body temperature in mice. (2016)
  • Author(s): Arata S, Watanabe J, Maeda M, Yamamoto M, Matsuhashi H, Mochizuki M, Kagami N, Honda K, Inagaki M.
  • Journal Title: Heliyon Volume: 2 Issue: 5 Pages: e00111-e00111
  • DOI: 10.1016/j.heliyon.2016.e00111
  • Peer Reviewed / Open Access
• [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] Scalable Production of a Multifunctional Protein (TSG-6) That Aggregates with Itself and the CHO Cells That Synthesize It. (2016)
  • Author(s): 11.Kim DK, Choi H, Nishida H, Oh JY, Gregory C, Lee RH, Yu JM, Watanabe J, An SY, Bartosh TJ, Prockop DJ.
  • Journal Title: PLoS One. Volume: 11 Issue: 1 Pages: 1-20
  • DOI: 10.1371/journal.pone.0147553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP). (2015)
  • Author(s): Tsumuraya T, Ohtaki H, Song D, Sato A, Watanabe J, Hiraizumi Y, Nakamachi T, Xu Z, Dohi K, Hashimoto H, Atsumi T, Shioda S.
  • Journal Title: J Neuroinflammation. Volume: 12(1) Issue: 1 Pages: 35-35
  • DOI: 10.1186/s12974-015-0252-5
  • Peer Reviewed / Open Access
• [Journal Article] Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40. (2015)
  • Author(s): Karki P, Kurihara T, Nakamachi T, Watanabe J, Asada T, Oyoshi T, Shioda S, Yoshimura M, Arita K, Miyata A.
  • Journal Title: Mol Pain. Volume: 11(1) Pages: 6-6
  • DOI: 10.1186/s12990-015-0003-8
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin suppresses proliferation of fetal neural progenitor cells, and induces their differentiation into neurons. (2015)
  • Author(s): Watanabe J, Matsumoto M, Kageyama H, Murai N, Sasaki S, Hirako S, Wada N, Arata S, Shioda S
  • Journal Title: Peptides Volume: 69 Pages: 40-46
  • DOI: 10.1016/j.peptides.2015.03.014
  • Peer Reviewed
• [Journal Article] Administration of TSG-6 improves memory after traumatic brain injury in mice. (2013)
  • Author(s): Watanabe J, Shetty AK, Hattiangady B, Kim DK, Foraker JE, Nishida H, Prockop DJ.
  • Journal Title: Neurobiology of Disease Volume: 59 Pages: 86-99
  • DOI: 10.1016/j.nbd.2013.06.017
  • Peer Reviewed
• [Presentation] 腎内血管内皮の多様性の検討：低真空SEMによる腎生検パラフィン切片の三次元的解析． (2017)
  • Author(s): 本田一穂，南雲佑，種田積子，舟橋久幸，大滝博和，澤智華，渡邊潤，瀧本雅文，小田秀明，新田孝作，大塚成人
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎, 長崎
  • Year and Date: 2017-03-28
• [Presentation] 骨髄間葉系幹細胞（MSCs）は頭部外傷モデルマウスの血液脳関門破綻を抑制する (2017)
  • Author(s): 渡邊 潤，大滝 博和，矢倉 一道，本田 一穂，荒田 悟
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎, 長崎
  • Year and Date: 2017-03-28
• [Presentation] 脊髄損傷マウスにおける慢性的なケモカインとその受容体の発現の変動． (2017)
  • Author(s): 矢倉一道，大滝博和，圓谷智海，佐藤 敦，渡邊 潤，宮本和幸，平泉 裕，本田一穂
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎, 長崎
  • Year and Date: 2017-03-28
• [Presentation] MRIによるPin1遺伝子欠損マウスの脳の容量の解析． (2017)
  • Author(s): 大滝博和，渡邊 潤，矢倉一道，宮本和幸，土肥謙二，内田隆史，本田一穂．
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎, 長崎
  • Year and Date: 2017-03-28
• [Presentation] PACAP KOマウスにおける加齢に伴う脳内酸化傷害の増加と記憶学習行動の異常． (2017)
  • Author(s): 中町智哉，大滝博和，渡邊潤，松田恒平，塩田清二
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎, 長崎
  • Year and Date: 2017-03-28
• [Presentation] Relationship between anxiety behavior and respiration control as determined using optogenetics. (2017)
  • Author(s): Okuma N, Kanamaru M, Moriya R, Tanaka FK, Arata S, Watanabe J, Endou T, Yoshikawa A, Iizuka M, Izumizaki M. Relationship between anxiety behavior and respiration control as determined using optogenetics.
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: 浜松, 静岡
  • Year and Date: 2017-03-28
• [Presentation] Responses of human mesenchymal stem/stromal cells on brain ischemia. (2016)
  • Author(s): Ohtaki H, Taniguchi S, Tanaka Y, Watanabe J, Miyamoto K, Yoshikawa A, Dohi K, Honda K.
  • Organizer: Annual meeting Soceity for Neuroscience 2016
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2016-11-12
• [Presentation] 脳虚血マウスにおける移植ヒト骨髄間葉系幹・前駆細胞（hMSCs）の応答. (2016)
  • Author(s): 大滝博和，渡邊潤，宮本和幸，平泉裕，本田一穂.
  • Organizer: 第８９回日本生化学会大会
  • Place of Presentation: 仙台, 宮城
  • Year and Date: 2016-09-25
• [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: お台場, 東京
  • Year and Date: 2016-05-13
• [Presentation] PACAPはアクアポリン５を介して涙液分泌を促進する。 (2016)
  • Author(s): 中町智哉, 大滝博和, 関保，渡邊潤, 塩田清二
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: お台場, 東京
  • Year and Date: 2016-05-13
• [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: 東京
  • Year and Date: 2016-05-13
• [Presentation] マウスにおけるPACAPの液分泌促進作用 (2016)
  • Author(s): 中町智哉, 渡邊潤, 塩田清二
  • Organizer: 第121 日本解剖学会総会･全国学術集会
  • Place of Presentation: 郡山
  • Year and Date: 2016-03-28
• [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, 平泉裕, 本田一穂
  • Organizer: 第121 日本解剖学会総会･全国学術集会
  • Place of Presentation: 郡山
  • Year and Date: 2016-03-28
• [Presentation] PACAPによる神経幹細胞のラジアルグリアへの分化誘導作用 (2016)
  • Author(s): 渡邊潤, 大滝博和, 荒田悟, 本田一穂, 塩田清二
  • Organizer: 第121 日本解剖学会総会･全国学術集会
  • Place of Presentation: 郡山
  • Year and Date: 2016-03-28
• [Presentation] Pituitary adenylate cyclase-activating polypeptide promotes eccrine sweat secretion. (2015)
  • Author(s): Shun Sasaki, Jun Watanabe, Hirokazu Ohtaki, Akira Miyazaki, Seiji Shioda, Hirohiko Sueki
  • Organizer: 日本研究皮膚科学会 第40回年次学術大会・総会
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
• [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 / Invited
• [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] Involvment 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 in VIP, PACAP and Related Peptides.
  • Place of Presentation: Cappadokia, Turkey
  • Year and Date: 2015-09-21
  • 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 in VIP, PACAP and Related Peptides
  • Place of Presentation: Cappadokia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] PACAP contributes proliferation of hippocampal neural stem/progenitor cells after global ischemia in mice. (2015)
  • Author(s): Nakamachi T, Ohtaki H, Watanabe J, Shioda S.
  • Organizer: 12th International Symposium in VIP, PACAP and Related Peptides.
  • Place of Presentation: Cappadokia, 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: 東京
  • Year and Date: 2015-07-21
• [Presentation] 遊離中/長鎖脂肪酸受容体GPR40/FFAR1の脊髄痛覚伝達における役割 (2015)
  • Author(s): 栗原崇, カルキ・プラサンナ, 中町智哉, 渡邊潤, 朝田俊秀, 大吉達樹, 塩田清二, 吉村惠, 有田和徳, 宮田篤郎
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-15
• [Presentation] PACAPの唾液および汗分泌促進作用 (2015)
  • Author(s): 中町智哉, 渡邊潤, 佐々木駿, 塩田清二
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-15
• [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: 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: 東京
  • Year and Date: 2015-05-15
• [Presentation] Anti-inflammatory protein TSG-6 secreted by MSCs reduces neural damage and improves memory defects after traumatic brain injury in mice (2015)
  • Author(s): Jun Watanabe, Hirokazu Ohtaki, Minako Matsumoto, Norimitsu Murai, Shun Sasaki, Satoru Arata, Seiji Shioda
  • Organizer: 第１２０回日本解剖学総会・第９２回日本生理学大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Intravenous injection of the anti-inflammatory protein TSG-6 reduces neural damage after traumatic brain injury in mice.
  • Author(s): Watanabe J, Shetty AK, Hattiangady B, Kim DK and Prockop DJ.
  • Organizer: Sixth International Mesenchymal Stem/Progenitor Cells Symposium.
  • Place of Presentation: College Station, Texas, USA
• [Presentation] 頭部外傷モデルマウスの記憶障害に対する、骨髄間葉系幹細胞（MSCs）由来タンパク質TSG-6の改善効果の検討
  • Author(s): 渡邊潤、塩田清二、Darwin J. Prockop
  • Organizer: 日本解剖学会関東支部第101回学術集会
  • Place of Presentation: 東京、昭和大学
• [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
  • 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、自治医科大学
• [Book] PACAP and neural development. In: Pituitary Adenylate Cyclase Activating Polypeptide – PACAP, (Eds. Reglodi D and Tamas A) (2016)
  • Author(s): Watanabe J, Seki T, Shioda S
  • Publisher: Springer Nature (New York)
• [Book] Chapter 18E. "Vasoactive intestinal peptide". In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Watanabe J
  • Total Pages: 3
  • Publisher: Elsevier (USA)
• [Book] Chapter 18F. Peptide histidine isoleucine/methionine. In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Watanabe J
  • Total Pages: 2
  • Publisher: Elsevier (USA)
• [Patent(Industrial Property Rights)] TREATMENT OF BRAIN INJURY OR TRAUMA WITH TSG-6 PROTEIN (2013)
  • Inventor(s): PROCKOP D.J. et al.
  • Industrial Property Rights Holder: PROCKOP D.J. et al.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-10-17
  • Overseas