Neuro-regenerative effects of MSC and neuropeptide after traumatic brain injury

• Project/Area Number: 16K21372
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery; Emergency medicine
• Research Institution: Showa University
• Principal Investigator: Watanabe Jun 昭和大学, 医学部, 兼任講師 (50649069)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 頭部外傷 / 神経新生 / 間葉系幹細胞 / 神経ペプチド / 記憶障害 / 骨髄由来間葉系幹細胞 / 神経申請 / PACAP / 移植・再生医療 / 神経科学

Outline of Final Research Achievements

We investigated the effects of TSG-6 on neuro-regeneration after acute traumatic brain injury. The results clarified the administration of TSG-6 increased the doublecortin positive new born neurons. Then we tried to establish the chronic model of repeated head concussion. However, intracerebral hemorrhagesome caused the animal death in high rate. As the standard deviation of neural death was also huge, we could not fix the model condition. In addition, we tried to make PACAP receptor knock out mouse using crispr CAS9 sysitem. The results indicated the knock out of PACAP causes the death in fetal or new born phase.

Academic Significance and Societal Importance of the Research Achievements

本研究の研究成果から、間葉系幹細胞の分泌タンパク質であるTSG-6が頭部外傷後の神経の保護作用があるだけでなく、神経新生促進作用もあることが明らかとなった。頭部外傷は現在根治治療の方法がなく、TSG-6が新たな治療法となりうる可能性を示唆した。また、そのメカニズムにPACAPが関与している可能性を示唆した。

Research Products

• [Int'l Joint Research] Texas A&M Health Science Center(米国)
• [Int'l Joint Research] Texas A&M University(米国)
• [Int'l Joint Research] University of Copenhagen(Denmark)
• [Int'l Joint Research] TUTCM(中国)
• [Journal Article] A simplified enriched environment increases body temperature and suppresses cancer progression in mice (2020)
  • Author(s): WATANABE Jun、KAGAMI Nobuyuki、KAWAZOE Mamiko、ARATA Satoru
  • Journal Title: Experimental Animals Volume: 69 Issue: 2 Pages: 207-218
  • DOI: 10.1538/expanim.19-0099
  • NAID: 130007835072
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Intrapancreatic injection of human bone marrow-derived mesenchymal stem/stromal cells alleviates hyperglycemia and modulates the macrophage state in streptozotocin-induced type 1 diabetic mice. (2017)
  • Author(s): Murai N, Ohtaki H, Watanabe J, Xu Z, Sasaki S, Yagura K, Shioda S, Nagasaka S, Honda K, Izumizaki M.
  • Journal Title: PLoS One Volume: 12 Issue: 10 Pages: e0186637-e0186637
  • DOI: 10.1371/journal.pone.0186637
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] PACAPによる神経幹細胞のラジアルグリアを介したアストロサイトへの分化誘導作用 (2019)
  • Author(s): 渡邊潤, 大滝博和, 本田一穂, 荒田悟.
  • Organizer: 第124回日本解剖学会総会全国学術集会
• [Presentation] 血管特異的アクアポリン1遺伝子導入マウスの熱中症に対する効果 (2019)
  • Author(s): 大滝博和，宮本和幸，荒田悟，若山吉弘，鈴木恵輔，渡邊潤，本田一穂，土肥謙二.
  • Organizer: 第124回日本解剖学会総会 全国学術集会
• [Presentation] PACAPによる神経幹細胞のラジアルグリアを介したアストロサイトへの分化誘導作用. (2019)
  • Author(s): 渡邊潤,大滝博和, 本田一穂, 荒田悟
  • Organizer: 第１２４回日本解剖学会総会・全国学術集会 (新潟)
• [Presentation] 簡易型環境エンリッチメント飼育マウスにおけるがん増殖抑制効果 (2018)
  • Author(s): 渡邊潤, 松橋秀人, 加賀美信幸, 荒田悟
  • Organizer: 第65回日本実験動物学会総会 (富山)
• [Presentation] PACAP induces differentiation of neural progenitor cells into glial lineage via radial glia (2018)
  • Author(s): Jun Watanabe, Hirokazu Ohtaki, Satoru Arata, Seiji Shioda
  • Organizer: International GPCR symposium (Kyoto, Japan)
  • Int'l Joint Research
• [Presentation] 脊髄損傷後のケモカインの局在とヒト間葉系幹細胞を用いた組織修復への関与 (2018)
  • 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123回日本解剖学会総会・学術集会 (東京)
• [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.
  • 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] Effects of enriched environment on suppression of cancer progression in mice. (2017)
  • Author(s): Arata S, Watanabe J, Matsuhashi H, Kagami N.
  • Organizer: 第64回日本実験動物学会総会 （福島、郡山）
• [Presentation] Production of MCP-1 (CCL2) from human mesenchymal stem/stromal cells in ischemic brain (2017)
  • Author(s): Ohtaki H, Yagura K, Tanaka Y, Watanabe J, Miyamoto K, Hiraizumi Y, Dohi K, Honda K.
  • Organizer: 第40回日本神経科学大会（千葉、幕張）
• [Presentation] Administration of TSG-6 form MSCs improves memory after traumatic brain injury in mice. (2017)
  • Author(s): Watanabe J, Ohtaki H, Yagura K, Honda K, Arata S.
  • Organizer: 第40回日本神経科学大会（千葉、幕張）
• [Presentation] Regulation of CCL2 (MCP-1) expression from human mesenchymal stem/stromal cells after ischemia through inflammatory cytokines. (2017)
  • Author(s): Ohtaki H, Yagura K, Watanabe J, Miyamoto K, Dohi K, Honda K.
  • Organizer: 第60回日本神経化学会大会 (宮城, 仙台)
• [Presentation] Effects of enriched environment on suppression of cancer progression in mice. (2017)
  • Author(s): Arata S, Watanabe J, Matsuhashi H, Kagami N.
  • Organizer: 第76回日本癌学会学術総会 （神奈川、横浜）
• [Presentation] Administrations of mesenchymal stem/stromal cells (MSCs) produced beneficial effects in models of traumatic brain injury via prevention of blood brain barrier leakage. (2017)
  • Author(s): Watanabe J, Ohtaki H, Yagura K, Honda K, Arata S.
  • Organizer: Neuroscience 2017 (Washington DC, USA)
  • Int'l Joint Research
• [Presentation] Gene and cellular localizations of chemokines and their receptors after spinal cord injury(SCI) in mice. (2017)
  • Author(s): Yagura K, Ohtaki H, Tsumuraya T, Sato A, Watanabe J, Miyamoto K, Tanaka S, Hiraizumi Y, Kanzaki K, Honda K.
  • Organizer: Neuroscience 2017 (Washington DC, USA )
  • Int'l Joint Research
• [Presentation] Suppression of nitric oxide level from microglia by co-culturing with human mesenchymal stem/progenitor cells. (2017)
  • Author(s): Ohtaki H, Watanabe J, Yagura K, Miyamoto K, Hiraizumi Y, Honda K, Dohi K.
  • Organizer: Neuroscience 2017 (Washington DC, USA )
  • Int'l Joint Research
• [Presentation] Human mesenchymal stem/stromal cells express CCL2 (MCP-1) on ischemic hippocampal homogenate exposure (Tu-P10-16). (2017)
  • Author(s): Ohtaki H, Watanabe J, Yagura K, Miyamoto K, Iwakura Y, Dohi K, Honda K.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS2017) (Kanazawa, Japan)
  • Int'l Joint Research
• [Presentation] Expression patterns and distributions of chemokines and their receptors after spinal cord injury (SCI) in mice. (2017)
  • Author(s): Yagura K, Ohtaki H, Tsumuraya T, Sato A, Watanabe J, Hiraizumi Y, Honda K.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS2017) (Kanazawa, Japan)
  • Int'l Joint Research
• [Presentation] PACAP promotes sweat secretion in eccrine gland via PAC1R. (2017)
  • Author(s): Watanabe J, Sasaki S, Ohtaki H, Arata S Honda K, Shioda S.
  • Organizer: 13th International Symposium on VIP, PACAP and Related Peptides (Hong Kong, China)
  • Int'l Joint Research / Invited
• [Presentation] 脊髄損傷マウスにおけるケモカインの変動と役割. (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64回昭和大学学士会総会 (東京)
• [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. Responses of human mesenchymal stem/stromal cells on brain ischemia.
  • 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. 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.
  • 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