Development of regenerative medical technology for cartilage and meniscus using human synovial stem cells by reproducing natural healing ability of rodents

• Project/Area Number: 16H06262
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIZUNO Mitsuru 東京医科歯科大学, 統合研究機構, プロジェクト助教 (00733908)
• Research Collaborator: SEKIYA Ichiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2018: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2017: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2016: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: 滑膜組織 / 滑膜幹細胞 / 再生医療 / 半月板再生 / 間葉系幹細胞 / 自然治癒 / 局在解析 / 再生能 / 再生医学 / 関節病学 / 滑膜幹細胞局在 / 半月板

Outline of Final Research Achievements

Developing superior regenerative medicine technology for meniscal injuries and cartilage degeneration associated with osteoarthritis of the knee is awaited for a vast scale of patients estimated to be about 8.5 million people in Japan.
In this project, with regard to the phenomena that occur in the natural regeneration process of rodents, it was identified that the invasion of blood vessels is an important factor, the characteristics of each were analyzed, and a paper is currently in preparation. Based on these findings, purified cells were analyzed for each layer of synovial tissue. Cells with high capacity were identified and reported in an international journal. In addition, we also study the preservation technique required when administering cells contributing to regeneration, report it as a paper to an international journal, and are patent-pending.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会を迎えた我が国において健康寿命を延伸させるため、短期で実用化可能な運動器疾患に対する質の高い治療法開発が急務である。本研究課題で目指した新しい医療技術の開発については、得られた間接的な成果を元に、別課題にて臨床研究が実施されていること、特許を出願中であることから、すでに研究の社会還元が始まっている。また、複数の国際誌への報告を達成しており、世界への公開も行っている。本研究課題の直接的な成果については、投稿準備中であるが、着実な成果が得られた。

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] Initial cell plating density affects properties of human primary synovial mesenchymal stem cells (2018)
  • Author(s): Nakamura Kaori、Tsuji Kunikazu、Mizuno Mitsuru、Koga Hideyuki、Muneta Takeshi、Sekiya Ichiro
  • Journal Title: Journal of Orthopaedic Research? Volume: - Issue: 6 Pages: 1358-1367
  • DOI: 10.1002/jor.24112
  • Peer Reviewed
• [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] 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] 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] Petaloid recombinant peptide enhances in vitro cartilage formation by synovial mesenchymal stem cells. (2018)
  • Author(s): Naritomi M, Mizuno M, Katano H, Ozeki N, Otabe K, Komori K, Fujii S, Ichinose S, Tsuji K, Koga H, Muneta T, Sekiya I.
  • Journal Title: J Orthop Res. Volume: in press Issue: 6 Pages: 1-8
  • DOI: 10.1002/jor.24042
  • Peer Reviewed / Open Access
• [Journal Article] Anterior cruciate ligament-derived mesenchymal stromal cells have a propensity to differentiate into the ligament lineage (2018)
  • Author(s): Ogata Yusuke、Mabuchi Yo、Shinoda Kosuke、Horiike Yuta、Mizuno Mitsuru、Otabe Koji、Suto Eriko Grace、Suzuki Nobuharu、Sekiya Ichiro、Akazawa Chihiro
  • Journal Title: Regenerative Therapy Volume: 8 Pages: 20-28
  • DOI: 10.1016/j.reth.2017.12.001
  • Peer Reviewed / Open Access
• [Journal Article] High-sensitivity virus and mycoplasma screening test reveals high prevalence of parvovirus B19 infection in human synovial tissues and bone marrow (2018)
  • Author(s): Watanabe Ken、Otabe Koji、Shimizu Norio、Komori Keiichirou、Mizuno Mitsuru、Katano Hisako、Koga Hideyuki、Sekiya Ichiro
  • Journal Title: Stem Cell Research & Therapy Volume: 9 Issue: 1 Pages: 80-80
  • DOI: 10.1186/s13287-018-0811-7
  • 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] 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] TNFα promotes proliferation of human synovial MSCs while maintaining chondrogenic potential. (2017)
  • Author(s): Shioda M, Muneta T, Tsuji K, Mizuno M, Komori K, Koga H, Sekiya I.
  • Journal Title: PLoS One Volume: 12 Issue: 5 Pages: e0177771-e0177771
  • DOI: 10.1371/journal.pone.0177771
  • Peer Reviewed / Open Access
• [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] Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates. (2016)
  • Author(s): Kondo S, Muneta T, Nakagawa Y, Koga H, Watanabe T, Tsuji K, Sotome S, Okawa A, Kiuchi S, Ono H, Mizuno M, Sekiya I
  • Journal Title: J Orthop Res Volume: in press Issue: 6 Pages: 1274-1282
  • DOI: 10.1002/jor.23211
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 高静水圧印加処理による脱細胞化半月板と凍結融解処理半月板の特性解析 (2018)
  • Author(s): 水野 満, 渡部 直人, 中村 奈緒子, 松田 純平, 木村 剛, 岸田 晶夫, 関矢 一郎
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] 滑膜幹細胞コロニーにおける増殖曲線の解析 (2018)
  • Author(s): 水野 満, 片野 尚子, 下嵜 ゆり, 佐波 晶, 小森 啓一郎, 大関 信武, 小田邉 浩二, 関矢 一郎
  • Organizer: 日本組織培養学会第91回大会
• [Presentation] 内側半月板変性断裂に対する3D-MRIを用いた世代別大腿骨軟骨面積率の検討 (2018)
  • Author(s): 鈴木 聡, 大関 信武, 水野 満, 小田邉 浩二, 片野 尚子, 板井 善則, 桝本 潤, 古賀 英之, 大川 淳, 関矢 一郎
  • Organizer: 第91回日本整形外科学会学術総会
• [Presentation] MRI三次元解析ソフトウェアによる膝関節軟骨の経時的定量評価 (2018)
  • Author(s): 兵藤 彰信, 大関 信武, 水野 満, 小田邉 浩二, 片野 尚子, 板井 善則, 桝本 潤, 大川 淳, 古賀 英之, 関矢 一郎
  • Organizer: 第91回日本整形外科学会学術総会
• [Presentation] 半月板温存を目指した治療：半月板変性断裂に対する滑膜幹細胞移植 (2018)
  • Author(s): 関矢 一郎, 古賀 英之, 大関 信武, 小田邉 浩二, 片野 尚子, 水野 満, 堀江 雅史, 小森 啓一郎, 藤井 静花, 大川 淳, 宗田 大
  • Organizer: 第91回日本整形外科学会学術総会
• [Presentation] 東京医科歯科大学における細胞調製施設運営の現状と課題 (2018)
  • Author(s): 水野 満、片野 尚子、藤井 静花、辻 彩子、関矢 一郎、森尾 友宏
  • Organizer: 第17回 日本再生医療学会
  • Invited
• [Presentation] アカデミアにおける細胞調製施設運営の実例と課題 (2018)
  • Author(s): 辻 彩子、藤井 静花、片野 尚子、河野 ゆり、須藤 絵里子グレース、森 裕章、水野 満、赤澤 智宏、関矢 一 郎、森尾 友宏
  • Organizer: 第17回 日本再生医療学会
• [Presentation] 滑膜幹細胞を用いた半月板の再生 (2018)
  • Author(s): 関矢 一郎、片野 尚子、大関 信武、水野 満、小田邉 浩二、小森 啓一郎、藤井 静花、古賀 英之
  • Organizer: 第17回 日本再生医療学会
  • Invited
• [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, Yuji Kohno, Yoshihisa Kushida, Naoto Watanabe, Kenta Katagiri, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Yoshinori Itai, Jun Masumoto, Hideyuki Koga, Tomoyuki Saito, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Image Analysis Method to Predict Cell Proliferation at Early Phase for Autologous Synovial Stem Cell Transplantation. (2018)
  • Author(s): Mitsuru Mizuno, Hisako Katano, Yuri Shimozaki, Sho Sanami, Keiichiro Komori, Koji Otabe, Nobutake Ozeki, Kunikazu Tsuji, Koga Hideyuki, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Biomechanical Analysis of Meniscus Centralization for Extruded Meniscus after Meniscectomy. (2018)
  • Author(s): Yuji Kohno, Hideyuki Koga, Nobutake Ozeki, Junpei Matsuda, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Validations for Cartilage Thickness, Cartilage Area Ratio and Meniscus Volume in the Knee by 3D MRI Analysis. (2018)
  • Author(s): Yuji Kohno, Nobutake Ozeki, Akinobu Hyodo, So Suzuki, Hayato Aoki, Yoshihisa Kushida, Naoto Watanabe, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Yoshinori Itai, Jun Masumoto, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Can Decellularized Meniscus by High Hydrostatic Pressure be an Alternative to Meniscus Allograft? - Compared with Deep Frozen Meniscus. (2018)
  • Author(s): Naoto Watanabe, Mitsuru Mizuno, Jumpei Matsuda, Naoko Nakamura, Koji Otabe, Hisako Katano, Nobutake Ozeki, Yuji Kono, Tsuyoshi Kimura, Kunikazu Tsuji, Hideyuki Koga, Akio Kishida, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Cartilage Area Ratio"by MRI 3D Analysis Reveals Subtle Change of Cartilage Volume in Middle Aged Patients with Medeal Meniscus Degenerative Tear. (2018)
  • Author(s): So Suzuki, Nobutake Ozeki, Akinobu Hyodo, Hayato Aoki, Yoshihisa Kushida, Naoto Watanabe, Yuji Kohno, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Yoshinori Itai, Jun Masumoto, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Mri 3d Analysis For Discoid Lateral Meniscus Of The Knee (2018)
  • Author(s): Hayato Aoki, Nobutake Ozeki, Kohno yuji, Kushida Yoshihisa, Naoto Watanabe, Akinobu Hyodo, So Suzuki, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Yoshinori Itai, Jun Masumoto, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Pseudo Color Images and Volume Measurement of Cartilage by Optical Coherence Tomography in a Rat Meniscectomized Model. (2018)
  • Author(s): Yoshihisa Kushida, Koichiro Kishima Nobutake Ozeki, Mitsuru Mizuno, Hisako Katano, Kunikazu Tsuji, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Petaloid Recombinant Peptide Constructs the Framework of Cartilage Pellet and Promotes In Vitro Cartilage Formation. (2018)
  • Author(s): Mana Naritomi, Mitsuru Mizuno, Hisako Katano, Koji Otabe, Keiichiro Komori, Shizuka Fujii, Shizuko Ichinose, Nobutake Ozeki, Kunikazu Tsuji, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Comparison Of Canine Mesenchymal Stem Cells Derived From Synovium, Infrapatellar Fat Pad, Subcutaneous Adipose Tissue And Bone Marrow. (2018)
  • Author(s): Akari Sasaki, Mitsuru Mizuno, Koji Otabe, Hisako Katano, Kunikazu Tsuji, Hideyuki Koga, Manabu Mochizuki, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [Presentation] Investigation of Freezing Medium for Synovial Mesenchymal Stem Cells. (2018)
  • Author(s): Ryota Fujisawa, Mitsuru Mizuno, Hisako Katano, Koji Otabe, Keiichiro Komori, Shizuka Fujii, Nobutake Ozeki, Kunikazu Tsuji, Hideyuki Koga, Ichiro Sekiya.
  • Organizer: Orthopaedic Research Society 2018 Annual Meeting
• [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
• [Presentation] Complete human serum maintains viability and chondrogenic potential of human synovial stem cells: suitable condition for transplantation (2017)
  • Author(s): Mitsuru Mizuno, Hisako Katano, Koji Otabe, Keiichiro Komori, Yuji Kohno, Shizuka Fujii, Nobutake Ozeki, Masafumi Horie, Kunikazu Tsuji, Takeshi Muneta, Ichiro Sekiya
  • Organizer: Orthopaedic Research Society 2017 Annual Meeting
  • Place of Presentation: San Diego, California
  • Year and Date: 2017-03-19
  • Int'l Joint Research
• [Presentation] ヒト血清による保存は滑膜幹細胞の増殖・軟骨分化能を維持する (2017)
  • Author(s): 水野 満、片野 尚子、小森 啓一郎、藤井 静花、大関 信武、小田邉 浩二、関矢 一郎
  • Organizer: 第16回 日本再生医療学会
  • Place of Presentation: 仙台国際会議場(宮城県、仙台市)
  • Year and Date: 2017-03-07
• [Presentation] 顕微鏡位相差像を用いた細胞増殖性を早期に予測する画像診断法の検討 (2017)
  • Author(s): 水野 満、片野 尚子、下嵜 ゆり、岡崎 拓矢、佐波 晶、関矢 一郎
  • Organizer: 第90回 日本組織培養学会
• [Presentation] 滑膜幹細胞移植は半月板逸脱・内縁切除モデルで軟骨変性を抑制する：マイクロミニピッグでの検討 (2017)
  • Author(s): 水野満、片桐健太、中川裕介、関矢一郎
  • Organizer: 第160回 日本獣医学会
• [Presentation] 軟骨・半月板再生を目指した滑膜幹細胞移植における輸送・保存条件の検討 (2017)
  • Author(s): 水野 満、藤井 静花、小森 啓一郎、大関 信武、片野 尚子、小田邉 浩二、辻 邦和、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] 顕微鏡位相差像を用いた細胞増殖性を早期に予測する画像解析法の検討 (2017)
  • Author(s): 水野 満、片野 尚子、大関 信武、下嵜 ゆり、佐波 晶、小田邉 浩二、辻 邦和、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] ヒト血清を用いた高濃度滑膜幹細胞製剤の保存法開発 (2017)
  • Author(s): 水野 満、片野 尚子、小森 啓一郎、藤井 静花、大関 信武、小田邉 浩二、関矢 一郎
  • Organizer: 第44回 日本臓器保存生物医学会学術集会
• [Presentation] 滑膜幹細胞による半月板縫合術後の治癒促進 マイクロミニピッグでの検討 (2016)
  • Author(s): 水野 満、中川 裕介、関矢 一郎
  • Organizer: 第159回日本獣医学会学術集会
  • Place of Presentation: 日本大学 生物資源科学部(神奈川県、藤沢市)
  • Year and Date: 2016-09-16
• [Presentation] 核型異常を有する滑膜幹細胞の解析 (2016)
  • Author(s): 水野 満、古田 絢女、藤井 静花、小原 収、関矢 一郎
  • Organizer: 運動器再生研究会
  • Place of Presentation: 広島県医師会館(広島県、広島市)
• [Book] 動物細胞培養・自動化における トラブル発生原因と対策 (2017)
  • Author(s): 水野満、関矢一郎
  • Total Pages: 526
  • Publisher: 技術情報協会
  • ISBN: 9784861046841
• [Book] Bone Joint Nerve (2016)
  • Author(s): 水野 満, 関矢 一郎
  • Total Pages: 6
  • Publisher: アークメディア
• [Patent(Industrial Property Rights)] 滑膜由来ＭＳＣの保存方法の発明 (2017)
  • Inventor(s): 水野 満、関矢 一郎等
  • Industrial Property Rights Holder: 水野 満、関矢 一郎等
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-022739
  • Filing Date: 2017