Meniscus regeneration by autologous tendon with synovial mesenchymal stem cells -experiments using microminipig

• Project/Area Number: 16K10891
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ozeki Nobutake 東京医科歯科大学, 統合研究機構, プロジェクト助教 (10755359)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 半月板 / バイオメカニクス / 腱 / 軟骨 / 軟骨分化 / MRI / 腱移植 / 再生医学

Outline of Final Research Achievements

When we culture rat tendons with bone Morphogenetic Protein 2 (BMP-2), the tendon differentiated into cartilage-like tissue 1 week after the culture and we could observe chondrocyte within the tendon. This change was observed regardless of coculture with synovial mesenchymal stem cells, therefore, the original tendon cells possibly transdifferentiated into chondrocytes by BMP-2. We confirmed the biomechanical usefulness of load distribution of centralization technique for meniscus extrusion and tendon transplantation for meniscus defect which caused knee osteoarthritis using pig model with knee flexion angle 30, 45, 60, and 90 degrees. Lastly, we established the evidence for reconstruction of three dimensional image of MRI to evaluate the meniscus condition for clinical use. The meniscus injury was easily evaluated with 3D reconstructed MRI quantitatively and also T2 mapping qualitatively.

Academic Significance and Societal Importance of the Research Achievements

本邦で有症状者800万人を超える変形性膝関節症の病態における半月板の役割は重要であり、半月板損傷に対する一般的な治療である半月板切除術が行われた場合に生じる半月板欠損部に対する治療はない。本研究において、腱に軟骨細胞を誘導することができ、また移植時の生体力学的検証でも半月板として機能することを証明できたことは、半月板の代用材料として自家腱を用いる実現性を示すことになった。また、臨床ではMRIが非侵襲評価法として用いられるが、3次元画像を構築して半月板の構造を評価する方法を確立できたことは、半月板に対する治療の是非を検証するうえでも意義が大きい。

Research Products

• [Journal Article] Biomechanical analysis of the centralization procedure for extruded lateral menisci with posterior root deficiency in a porcine model. (2019)
  • Author(s): Nobutake Ozekia, Hideyuki Koga, Junpei Matsuda, Yuji Kohno, Mitsuru Mizuno,Hisako Katano, Kunikazu Tsuji, Tomoyuki Saito, Takeshi Muneta, Ichiro Sekiya
  • Journal Title: Journal of Orthopaedic Science Volume: 印刷中 Issue: 1 Pages: 161-166
  • DOI: 10.1016/j.jos.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Specific markers and properties of synovial mesenchymal stem cells in the surface, stromal, and perivascular regions. (2018)
  • Author(s): Mizuno M, Katano H, Mabuchi Y, Ogata Y, Ichinose S, Fujii S, Otabe K, Komori K, Ozeki N, Koga H, Tsuji K, Akazawa C, Muneta T, Sekiya I.
  • Journal Title: Stem Cell Res Ther. Volume: 9 Issue: 1 Pages: 123-123
  • DOI: 10.1186/s13287-018-0870-9
  • Peer Reviewed / Open Access
• [Journal Article] Trends in isolated meniscus repair and meniscectomy in Japan, 2011-2016 (2018)
  • Author(s): Katano Hisako、Koga Hideyuki、Ozeki Nobutake、Otabe Koji、Mizuno Mitsuru、Tomita Makoto、Muneta Takeshi、Sekiya Ichiro
  • Journal Title: Journal of Orthopaedic Science Volume: 23 Issue: 4 Pages: 676-681
  • DOI: 10.1016/j.jos.2018.04.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Canine mesenchymal stem cells from synovium have a higher chondrogenic potential than those from infrapatellar fat pad, adipose tissue, and bone marrow (2018)
  • Author(s): Sasaki Akari、Mizuno Mitsuru、Ozeki Nobutake、Katano Hisako、Otabe Koji、Tsuji Kunikazu、Koga Hideyuki、Mochizuki Manabu、Sekiya Ichiro
  • Journal Title: PLOS ONE Volume: 13 Issue: 8 Pages: e0202922-e0202922
  • DOI: 10.1371/journal.pone.0202922
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of mesenchymal stem cells obtained by suspended culture of synovium from patients with rheumatoid arthritis and osteoarthritis. (2018)
  • Author(s): Yuji Kohno, Mitsuru Mizuno, Nobutake Ozeki, Hisako Katano, Koji Otabe, Hideyuki Koga, Mikio Matsumoto, Haruka Kaneko, Yuji Takazawa, Ichiro Sekiya
  • Journal Title: BMC Musculoskelet Disord Volume: 19 Issue: 1 Pages: 78-78
  • DOI: 10.1186/s12891-018-1998-6
  • Peer Reviewed / Open Access
• [Journal Article] Transplantation of synovial mesenchymal stem cells for cartilage and meniscus regeneration (2018)
  • Author(s): Nobutake Ozeki, Hideyuki Koga, Ichiro Sekiya
  • Journal Title: Clin Calcium Volume: 28 Pages: 319-327
  • Peer Reviewed
• [Journal Article] Fibrous synovium releases higher numbers of mesenchymal stem cells than adipose synovium in a suspended synovium culture model. (2017)
  • Author(s): Kenta Katagiri, Yu Matsukura, Takeshi Muneta, Nobutake Ozeki, Mitsuru Mizuno, Hisako Katano, Ichiro Sekiya
  • Journal Title: Arthroscopy Volume: 33 Issue: 4 Pages: 800-810
  • DOI: 10.1016/j.arthro.2016.09.033
  • Peer Reviewed / Open Access
• [Journal Article] Centralization of extruded medial meniscus delays cartilage degeneration in rats. (2017)
  • Author(s): Ozeki N, Muneta T, Kawabata K, Koga H, Nakagawa Y, Saito R, Udo M, Yanagisawa K, Ohara T, Mochizuki T, Tsuji K, Saito T, Sekiya I.
  • Journal Title: J Orthop Sci. Volume: in press Issue: 3 Pages: 542-548
  • DOI: 10.1016/j.jos.2017.01.024
  • Peer Reviewed / Open Access
• [Journal Article] Yields and chondrogenic potential of primary synovial mesenchymal stem cells are comparable between rheumatoid arthritis and osteoarthritis patients. (2017)
  • Author(s): Yuji Kohno, Mitsuru Mizuno, Nobutake Ozeki, Hisako Katano, Keiichiro Komori, Shizuka Fujii, Koji Otabe, Masafumi Horie, Hideyuki Koga, Kunikazu Tsuji, Mikio Matsumoto, Haruka Kaneko, Yuji Takazawa, Takeshi Muneta, Ichiro Sekiya
  • Journal Title: Stem Cell Res Ther Volume: 8 Issue: 1 Pages: 115-115
  • DOI: 10.1186/s13287-017-0572-8
  • Peer Reviewed / Open Access
• [Journal Article] Complete human serum maintains viability and chondrogenic potential of human synovial stem cells: suitable conditions for transplantation. (2017)
  • Author(s): Mitsuru Mizuno, Hisako Katano, Koji Otabe, Keiichiro Komori, Yuji Kohno, Shizuka Fujii, Nobutake Ozeki, Masafumi Horie, Kunikazu Tsuji, Hideyuki Koga, Takeshi Muneta, Ichiro Sekiya
  • Journal Title: Stem Cell Res Ther Volume: 8 Issue: 1 Pages: 144-144
  • DOI: 10.1186/s13287-017-0596-0
  • Peer Reviewed / Open Access
• [Journal Article] 滑膜間葉系幹細胞の定期的関節内投与は変形性膝関節症の進行を抑制する (2017)
  • Author(s): 大関 信武, 宗田 大, 齋藤 知行, 関矢 一郎
  • Journal Title: 再生医療 Volume: 16 Pages: 241-248
• [Journal Article] Strenuous running exacerbates knee cartilage erosion induced by low amount of mono-iodoacetate in rats. (2017)
  • Author(s): Saito R, Muneta T, Ozeki N, Nakagawa Y, Udo M, Yanagisawa K, Tsuji K, Tomita M, Koga H, Sekiya I.
  • Journal Title: BMC Musculoskelet Disord. Volume: 18 Issue: 1 Pages: 36-36
  • DOI: 10.1186/s12891-017-1393-8
  • Peer Reviewed / Open Access
• [Journal Article] 早期変形性膝関節症の概念 (2016)
  • Author(s): 大関信武
  • Journal Title: Bone Joint Nerve Volume: 6 Pages: 473-479
• [Journal Article] 変形性膝関節症に対する幹細胞の関節内投与 ラットモデルでの解析 (2016)
  • Author(s): 大関信武
  • Journal Title: Bone Joint Nerve Volume: 6 Pages: 579-588
• [Presentation] マイクロミニピッグ半月板変性断裂モデルにおいて滑膜幹細胞投与は滑膜被覆による癒合を促進する (2018)
  • Author(s): 大関 信武
  • Organizer: 第33回日本整形外科学会基礎学術集会
• [Presentation] Three-Dimensional MRI, T2 Mapping and Histological Analyses of Meniscus Repair After Transplantation of Synovial Mesenchymal Stem Cells in a Novel Degenerative Meniscus Injury Model in Pig. (2018)
  • Author(s): Nobutake Ozeki
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] 三次元MRI画像による半月板高輝度像の解析 マイクロミニピッグ半月板変性モデル・滑膜幹細胞投与での解析 (2018)
  • Author(s): 大関 信武
  • Organizer: 第10回日本関節鏡・膝・スポーツ整形外科学会
• [Presentation] Effects of synovial stem cells and BMP-2 on cartilage formation of tendon. (2018)
  • Author(s): Miharu Ochi, Nobutake Ozeki, Mitsuru Mizuno, Hisako Katano, Kunikazu Tsuji, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] 半月板逸脱に対するCentralization法の生体力学的解析 (2017)
  • Author(s): 大関 信武, 宗田 大, 古賀 英之, 河野 佑二, 片桐 健太, 齋藤 知行, 関矢 一郎
  • Organizer: 第9回日本関節鏡・膝・スポーツ整形外科学会
• [Presentation] 早期変形性膝関節症の診断 どれくらい早期に診断できるのか 早期変形性膝関節症の概念 (2017)
  • Author(s): 大関 信武, 宗田 大, 齋藤 知行, 関矢 一郎
  • Organizer: 第9回日本関節鏡・膝・スポーツ整形外科学会
• [Presentation] マイクロミニピッグ半月板損傷モデルにおける滑膜幹細胞関節内投与の効果：三次元MRI解析を用いた半月板の評価 (2017)
  • Author(s): 大関 信武, 河野 佑二, 宗田 大, 串田 淑久, 渡部 直人, 片桐 健太, 水野 満, 片野 尚子, 板井 善則, 桝本 潤, 古賀 英之, 齋藤 知行, 大川 淳, 関矢 一郎
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] 軟骨分化誘導させた滑膜幹細胞／腱複合体による半月板再建 (2017)
  • Author(s): 越智 美晴, 大関 信武, 水野 満, 宗田 大, 大川 淳, 関矢 一郎
  • Organizer: 第32回日本整形外科学会基礎学術集会
• [Presentation] 半月板欠損部に対する自家腱による半月板再建術の荷重分散におけるバイオメカニクス (2016)
  • Author(s): 大関信武
  • Organizer: 日本臨床バイオメカニクス学会
  • Place of Presentation: かでる2・7 北海道 札幌市
  • Year and Date: 2016-10-13
• [Presentation] 半月板付着部の損傷に対する修復術の効果 (2016)
  • Author(s): 大関信武
  • Organizer: 日本整形外科基礎学術集会
  • Place of Presentation: 福岡国際会議場 福岡県 福岡市
  • Year and Date: 2016-10-09
• [Presentation] 半月板逸脱に対するCentralization法のバイオメカニクス評価 (2016)
  • Author(s): 大関信武
  • Organizer: 日本整形外科学会
  • Place of Presentation: パシフィコ横浜 神奈川県 横浜市
  • Year and Date: 2016-05-14