The molecular biological analysis of spinal cord related pain and the assessment of spinal cord function using neuroimaging

• Project/Area Number: 24390351
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: University of Fukui
• Principal Investigator: UCHIDA Kenzo 福井大学, 医学部, 准教授 (60273009)
• Co-Investigator(Kenkyū-buntansha): BABA Hisatoshi 福井大学, 医学部, 教授 (00165060) ; NAKAJIMA Hideaki 福井大学, 医学部, 助教 (10397276) ; USHIDA Takahiro 愛知医科大学, 医学部, 教授 (60304680)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2012: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000)
• Keywords: 脊髄損傷 / 神経障害性疼痛 / 遺伝子解析 / 画像解析 / 活性型ミクログリア

Outline of Final Research Achievements

We investigated the effects of bone marrow-derived mesenchymal stem cells (BMSC) transplantation on pain hypersensitivity in GFP-positive bone marrow-chimeric mice subjected to a contusion spinal cord injury (SCI). BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities. The pain improvements were mediated by suppression of PKC-γ and p-CREB expression in dorsal horn neurons. BMSC transplants significantly reduced levels of mitogen activated protein kinase (MAPK) signaling (p-p38 MAPK and p-ERK1/2) in both hematogenous macrophages and resident microglia. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB); reduced leakage of albumin and PDGFR-α immunoreactivity at day 7 post-SCI, which was associated with decreased levels of inflammatory cytokines. These changes is likely to play a major role in reducing pain hypersensitivity in the BMSC treated SCI animals.

Research Products

• [Journal Article] Early Transplantation of Mesenchymal Stem Cells after Spinal Cord Injury Relieves Pain Hypersensitivity Through Suppression of Pain‐ Related Signaling Cascades and Reduced Inflammatory Cell Recruitment (2015)
  • Author(s): S Watanabe, K Uchida, H Nakajima, H Matsuo, D Sugita, A Yoshida, K Honjoh, Johnson WE, H Baba
  • Journal Title: Stem Cells Volume: in press Issue: 6 Pages: 1902-1914
  • DOI: 10.1002/stem.2006
  • Peer Reviewed / Open Access
• [Journal Article] 慢性圧迫脊髄における疼痛発現に関する基礎的研究―twy chimeric mouseを用いて― (2014)
  • Author(s): 竹浦直人, 内田研造, 中嶋秀明, 渡邉修司, 吉田藍, 馬場久敏
  • Journal Title: 厚生労働科学研究費補助金 難治性疾患等克服研究事業 脊柱靭帯骨化症に関する調査研究 平成25年度 総括・分担研究報告書 Volume: 2014 Pages: 47-50
• [Journal Article] FDG-PETによる脊髄機能評価 (2014)
  • Author(s): 中嶋秀明, 内田研造, 馬場久敏
  • Journal Title: Bone Joint Nerve 特集「整形外科イメージングの進歩」 Volume: 4(2) Pages: 223-229
  • Open Access
• [Journal Article] Gene therapy strategies for the treatment of spinal cord injury (2014)
  • Author(s): K Uchida, H Nakajima, Alexander Guerrero, William EB Johnson, Wagih El Masri, H Baba
  • Journal Title: Ther Deliv Volume: 5(5) Issue: 5 Pages: 591-607
  • DOI: 10.4155/tde.14.20
  • Peer Reviewed / Open Access
• [Journal Article] Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain (2014)
  • Author(s): H Matsuo, K Uchida, H Nakajima, Alexander Guerrero, S Watanabe, N Takeura, D Sugita, S Shimada, T Nakatsuka, H Baba
  • Journal Title: Pain Volume: 155(9) Issue: 9 Pages: 1888-1901
  • DOI: 10.1016/j.pain.2014.06.022
  • Peer Reviewed / Open Access
• [Journal Article] The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: Implications for human cervical compressive myelopathy (2013)
  • Author(s): T.Hirai, K.Uchida, H.Nakajima, Alexander Guerrero, N.Takeura, S.Watanabe, D.Sugita, A.Yoshida, W.E.Johnson, H.Baba
  • Journal Title: PLoS One Volume: 8(5) Issue: 5 Pages: e64528-e64528
  • DOI: 10.1371/journal.pone.0064528
  • Peer Reviewed
• [Journal Article] Blockade of interleukin 6 signaling improves the survival rate of transplanted bone marrow stromal cells and increases locomotor function in mice with spinal cord injury (2013)
  • Author(s): Tan Ying, K.Uchida, H.Nakajima, Alexander Guerrero, S.Watanabe, T.Hirai, N.Takeura, Lui Shao-Yu, Johnson William E.B., H.Baba
  • Journal Title: J Neuropathol Exp Neurol Volume: 72（10） Issue: 10 Pages: 980-993
  • DOI: 10.1097/nen.0b013e3182a79de9
  • Peer Reviewed
• [Journal Article] 慢性圧迫脊髄における疼痛発現に関する基礎的研究―twy chimeric mouseを用いて― (2013)
  • Author(s): 竹浦 直人, 内田 研造, 中嶋 秀明, 渡邉 修司, 吉田 藍, 馬場 久敏
  • Journal Title: 厚生労働科学研究費補助金 難治性疾患等克服研究事業 脊柱靭帯骨化症に関する調査研究 平成25年度 総括・分担研究報告書 Volume: H25 Pages: 47-50
• [Journal Article] 慢性脊髄圧迫モデル（twy/twy mouse）を用いた脊髄後角におけるMAPK pathway に関する免疫組織学的検討 (2013)
  • Author(s): 竹浦 直人, 内田 研造, 中嶋 秀明, 平井 貴之, 渡邉 修司, 馬場 久敏
  • Journal Title: 中部整災誌 Volume: 56(5) Pages: 1117-1118
  • NAID: 130004144147
• [Presentation] 脊髄圧迫・損傷における神経生物学的可塑性と再生医学的応答 (2014)
  • Author(s): 馬場久敏, 中嶋秀明, 竹浦直人, 吉田藍, 渡邉修司, 犬飼智雄, William E B Johnson, 内田研造
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 鹿児島市、城山観光ホテル
  • Year and Date: 2014-10-09 – 2014-10-10
  • Invited
• [Presentation] GFPマウス骨髄を移植したtwyキメラマウスを用いた慢性疼痛に関する免疫組織学的検討 (2014)
  • Author(s): 竹浦直人, 内田研造, 中嶋秀明, 渡邉修司, 吉田藍, 本定和也, 馬場久敏
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 鹿児島市、城山観光ホテル
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] 脊髄障害性疼痛におけるミクログリア/マクロファージの活性化分子メカニズム (2014)
  • Author(s): 内田研造, 中嶋秀明, 馬場久敏
  • Organizer: 第29回日本整形外科学会基礎学術集会
  • Place of Presentation: 鹿児島市、城山観光ホテル
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] Chronic progressive compression induces the phenotype changes of the activated microglia/macrophages in the spinal cord of spinal hyperostotic twy/twy mouse: Implications in human cervical compressive myelopathy (2014)
  • Author(s): T Hirai, K Uchida, H Nakajima, T Inukai, N Takeura, S Watanabe, H Baba
  • Organizer: Euro Spine 2014
  • Place of Presentation: Lyon（France）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Quantitative analysis and prognostic value of changes in spinal cord signal intensity on magnetic resonance imaging in patients with cervical compressive myelopathy (2014)
  • Author(s): H Nakajima, K Uchida, N Takeura, K Honjoh, T Sakamoto, H Baba
  • Organizer: Euro Spine 2014
  • Place of Presentation: Lyon（France）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment (2014)
  • Author(s): K Uchida, H Nakajima, S Watanabe, K Honjoh, William E B Johnson, H Baba
  • Organizer: The 16th Spinal Research Network Meeting
  • Place of Presentation: London（United Kingdom）
  • Year and Date: 2014-09-05 – 2014-09-06
• [Presentation] Blockade of interleukin-6 signaling improves the survival rate of transplanted bone marrow stromal cells and increases locomotory function in mice with spinal cord injury (2013)
  • Author(s): K.Uchida, H.Nakajima, Ying Tan, S.Watanabe, M.Kitade, William E. B. Johnson, H.Baba
  • Organizer: The 15th Spinal Research Network Meeting
  • Place of Presentation: London UK
• [Presentation] Dynamic state and localization of microglia in injured spinal cord by the peripheral benzodiazepine receptor ligand PK11195 (2013)
  • Author(s): S.Watanabe, K.Uchida, H.Nakajima, T.Hirai, H.Baba
  • Organizer: Euro Spine 2013
  • Place of Presentation: Liverpool UK
• [Presentation] 脊髄障害性疼痛症候群の実態の把握と病態の解明に関する研究―全国二次アンケート調査の結果報告― (2013)
  • Author(s): 内田 研造, 馬場 久敏, 中嶋 秀明, 田口 敏彦, 山下 敏彦, 中村 雅也, 牛田 享宏
  • Organizer: 第86回日本整形外科学会学術総会
  • Place of Presentation: 広島県 広島市 広島グリーンアリーナ
• [Presentation] 脊髄損傷モデルの慢性疼痛の解析および骨髄間質細胞移植の与える効果についての検討 (2013)
  • Author(s): 渡邉 修司, 内田 研造, 中嶋 秀明, 吉田 藍, 竹浦 直人, 馬場 久敏
  • Organizer: 第42回日本脊椎脊髄病学会
  • Place of Presentation: 沖縄県 宜野湾市 沖縄コンベンションセンター
• [Presentation] 脊髄損傷後疼痛に対する骨髄間質細胞移植の有効性の検討 (2013)
  • Author(s): 渡邉 修司, 内田 研造, 中嶋 秀明, 松尾 英明, 竹浦 直人, 吉田 藍, 馬場 久敏
  • Organizer: 第28回日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉県 千葉市 幕張メッセ
• [Presentation] マウス脊髄損傷モデルに対するPK11195トレーサーを用いた活性化ミクロクリアの組織学的検討 (2012)
  • Author(s): 渡邉修司
  • Organizer: 第27回日本整形外科学会基礎学術集会
  • Place of Presentation: 名古屋市
• [Presentation] 脊髄損傷後マウス慢性疼痛に対する骨髄間質細胞移植の有効性 (2012)
  • Author(s): 渡邉修司
  • Organizer: 第5回日本運動器疼痛学会
  • Place of Presentation: 東京都
• [Book] Case Library Series 痛みの診療 ベストプラクティス (2014)
  • Author(s): 中嶋秀明, 内田研造, 馬場久敏
  • Total Pages: 159
  • Publisher: 株式会社メディカルレビュー社
• [Book] Neuroprotection and Regeneration of the Spinal Cord (2014)
  • Author(s): K Uchida, H Nakajima, T Hirai, Sally Roberts, William E B Johnson, H Baba
  • Total Pages: 419
  • Publisher: Springer
• [Book] Neuroprotection and Regeneration of the Spinal Cord (2014)
  • Author(s): H Nakajima, K Uchida, Alexander Guerrero, S Watanabe, D Sugita, N Takeura, A Yoshida, H Baba
  • Total Pages: 419
  • Publisher: Springer
• [Book] Neuroprotection and Regeneration of the Spinal Cord (2014)
  • Author(s): K Uchida, H Nakajima, H Okazawa, H Kimura, A Yoshida, H Baba
  • Total Pages: 419
  • Publisher: Springer
• [Book] ペインクリニシャンのための新キーワード 135 (2014)
  • Author(s): 中嶋秀明, 内田研造, 馬場久敏, 牛田享宏
  • Total Pages: 342
  • Publisher: 真興交易（株）医書出版部