Molecular mechanisms of proliferation and differentiation of mesenchymal stem cells

• Project/Area Number: 15K10464
• 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: KOGA Hideyuki 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (30594080)
• Co-Investigator(Kenkyū-buntansha): 辻 邦和 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (20323694) ; 宗田 大 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50190864) ; 関矢 一郎 東京医科歯科大学, 統合研究機構, 教授 (10345291)
• Research Collaborator: SEKIYA Ichiro 東京医科歯科大学, 再生医療研究センター, 教授 (10345291)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: MSC / synovium / Proliferation / Differentiation / PI3K / PDGF / chondrogenesis / surface antigen / 間葉系幹細胞 / 表面抗原 / Synovium / Mesenchymal stem cell / Multipotency / Mesenchymal Stem Cell / Surface Antigen

Outline of Final Research Achievements

Platelet-derived growth factors (PDGFs) have been reported to enhance proliferation of synovial mesenchymal stem cells (MSCs) without reducing their multipotency. This study was aimed to elucidate the intracellular molecular pathways activated by PDGFs. Synovial MSCs were isolated from patients who underwent total knee arthroplasty. Cell proliferation and differentiation assays were performed in the presence of inhibitors specific for intracellular kinases. Both PDGF-AA and -BB enhanced cell proliferation in medium containing reduced serum. These effects were significantly reduced by a PI3K inhibitor, LY290042. During in vitro chondrogenesis, LY290042 significantly reduced the size of spheroids enhanced by PDGF-AA. LY290042 also significantly inhibited in vitro chondrogenic and osteoblastic differentiation. Our data indicated that activation of the PI3K-PKB/Akt pathway by PDGFs plays an important role in both proliferation and differentiation of synovial MSCs.

Research Products

• [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] 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] Hyperbaric oxygen reduces inflammation, oxygenates injured muscle, and regenerates skeletal muscle via macrophage and satellite cell activation (2018)
  • Author(s): Oyaizu Takuya、Enomoto Mitsuhiro、Yamamoto Naoki、Tsuji Kunikazu、Horie Masaki、Muneta Takeshi、Sekiya Ichiro、Okawa Atsushi、Yagishita Kazuyoshi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1288-1288
  • DOI: 10.1038/s41598-018-19670-x
  • Peer Reviewed / Open Access
• [Journal Article] PDGF-induced proliferation and differentiation of synovial mesenchymal stem cells is mediated by the PI3K-PKB/Akt pathway. (2018)
  • Author(s): Uomizu M, Muneta T, Ojima M, Sekiya I, Koga H, Tsuji K.
  • Journal Title: J Med Dent Sci. Volume: accepted
  • NAID: 130007410291
  • Peer Reviewed
• [Journal Article] Effects of different cell detaching methods on the viability and cell surface antigen expression of synovial mesenchymal stem cells. (2017)
  • Author(s): Tsuji K, Ojima M, Otabe K, Horie M, Koga H, Sekiya I, Muneta T.
  • Journal Title: Cell Transplant. Volume: in press Issue: 6 Pages: 1089-1102
  • DOI: 10.3727/096368917x694831
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pretreatment with IL1β enhances proliferation and chondrogenic potential of synoviumderived mesenchymal stem cells. (2017)
  • Author(s): Matsumura E
  • Journal Title: Cytotherapy. Volume: 19(2) Issue: 2 Pages: 181193-181193
  • DOI: 10.1016/j.jcyt.2016.11.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <Original Article>Hypoxia enhances proliferation through increase of colony formation rate with chondrogenic potential in primary synovial mesenchymal stem cells (2016)
  • Author(s): Ohara T, Muneta T, Nakagawa Y, Matsukura Y, Ichinose S, Koga H, Tsuji K, Sekiya I.
  • Journal Title: Journal of Medical and Dental Sciences Volume: 63 Issue: 4 Pages: 61-70
  • DOI: 10.11480/jmds.630401
  • NAID: 130006944182
  • ISSN: 1342-8810, 2185-9132
  • Peer Reviewed
• [Journal Article] Weekly injections of Hylan G-F 20 delay cartilage degeneration inpartial meniscectomized rat knees. (2016)
  • Author(s): Yanagisawa K, Muneta T, Ozeki N, Nakagawa Y, Udo M, Saito R, Koga H, Tsuji K, Sekiya I
  • Journal Title: BMC Musculoskelet Disord. Volume: 17 Issue: 1 Pages: 188-188
  • DOI: 10.1186/s12891-016-1051-6
  • 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
• [Journal Article] Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. (2016)
  • Author(s): Ozeki N, Muneta T, Koga H, Nakagawa Y, Mizuno M, Tsuji K, Mabuchi Y, Akazawa C, Kobayashi E, Matsumoto K, Futamura K, Saito T, Sekiya I
  • Journal Title: Osteoarthritis Cartilage Volume: in press Issue: 6 Pages: 1061-70
  • DOI: 10.1016/j.joca.2015.12.018
  • NAID: 40021330438
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Platelet-derived growth factor (PDGF)-AA/AB in human serum are potential indicators of the proliferative capacity of human synovial mesenchymal stem cells. (2015)
  • Author(s): Mizuno M, Katano H, Otabe K, Komori K, Matsumoto Y, Fujii S, Ozeki N, Tsuji K, Koga H, Muneta T, Matsuyama A, Sekiya
  • Journal Title: Stem Cell Res Ther. Volume: 10 Issue: 1 Pages: 243-243
  • DOI: 10.1186/s13287-015-0239-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synovial mesenchymal stem cells promote meniscus regeneration augmented by an autologous Achilles tendon graft in a rat partial meniscus defect model. (2015)
  • Author(s): Ozeki N, Muneta T, Matsuta S, Koga H, Nakagawa Y, Mizuno M, Tsuji K, Mabuchi Y, Akazawa C, Kobayashi E, Saito T, Sekiya I.
  • Journal Title: Stem Cells. Volume: 33(6) Issue: 6 Pages: 1927-38
  • DOI: 10.1002/stem.2030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age. (2015)
  • Author(s): Abula K, Muneta T, Miyatake K, Yamada J, Matsukura Y, Inoue M, Sekiya I, Graf D, Economides AN, Rosen V, Tsuji K.
  • Journal Title: FEBS Lett. Volume: in press Issue: 11 Pages: 197-200
  • DOI: 10.1016/j.febslet.2015.04.004
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 滑膜由来間葉系幹細胞はラットの肩腱板修復を促進する (2017)
  • Author(s): 魚水 麻里, 望月 智之, 辻 邦和, 古賀 英之, 大関 信武, 大原 敏之, 松田 純平, 後藤 昌史, 関矢 一郎, 宗田 大.
  • Organizer: 第３２回日本整形外科学会基礎学術集会.
• [Presentation] ラット膝関節炎疼痛モデルを用いた膝関節における免疫組織学的検討および行動評価:低用量および高用量モノヨード酢酸による比較. (2017)
  • Author(s): 星野 傑, 辻 邦和, 小沼 博明, 片桐 洋樹, 宮武 和正, 宇土 美於, 魚水 麻里, 植木 博子, 猪野又 慶, 大川 淳, 関矢 一郎, 古賀 英之, 宗田 大.
  • Organizer: 第３２回日本整形外科学会基礎学術集会.
• [Presentation] MIAで誘導された膝蓋下脂肪体の線維化と血管新生は、膝関節周囲痛の慢性化と共に有意に増加する. (2017)
  • Author(s): 小沼 博明, 辻 邦和, 星野 傑, 片桐 洋樹, 宮武 和正, 大川 淳, 関矢 一郎, 古賀 英之, 宗田 大.
  • Organizer: 第３２回日本整形外科学会基礎学術集会.
• [Presentation] 関節液中に存在しヒト間葉系幹細胞の増殖を促進する生理活性物質(Factor A)の同定と生理機能解析. (2017)
  • Author(s): 尾島 美代子, 辻 邦和, 宮武 和正, 片桐 洋樹, 堀江 雅史, 古賀 英之, 大川 淳, 関矢 一郎, 宗田 大.
  • Organizer: 第３２回日本整形外科学会基礎学術集会.
• [Presentation] モノヨード酢酸によるラット関節炎モデルにおいて炎症期の滑膜幹細胞投与の軟骨変性および疼痛に対する効果の検討 (2016)
  • Author(s): 宇土美於、辻邦和、星野傑、関矢一郎、宗田大
  • Organizer: 第9回 日本運動器疼痛学会
  • Place of Presentation: 御茶ノ水ソラシティーカンファレンスセンター、東京都千代田区
  • Year and Date: 2016-11-26
• [Presentation] 低用量および高用量モノヨード酢酸を用いたラット膝関節炎疼痛モデルにおける疼痛行動評価及び組織学的検討 (2016)
  • Author(s): 星野傑、辻邦和、宇土美於、関矢一郎、宗田大
  • Organizer: 第9回 日本運動器疼痛学会
  • Place of Presentation: 御茶ノ水ソラシティーカンファレンスセンター、東京都千代田区
  • Year and Date: 2016-11-26
• [Presentation] 低用量モノヨード酢酸を用いたラット膝関節炎疼痛モデルにおける疼痛行動評価及び組織学的検討 (2016)
  • Author(s): 星野傑、辻邦和、宇土美於、関矢一郎、宗田大
  • Organizer: 第31回 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: 2016-10-13
• [Presentation] Different methods of detaching adherent cells significantly affect the detection of stem cell antigens in synovial mesenchymal stem cells. (2016)
  • Author(s): Miyoko Ojima, Kunikazu Tsuji, Koji Otabe, Masafumi Horie, Hideyuki Koga, Ichiro Sekiya, and Takeshi Muneta
  • Organizer: Osteoarthritis Research Society International
  • Place of Presentation: Amsterdam Netherlands
  • Year and Date: 2016-03-31
  • Int'l Joint Research
• [Presentation] Dynamic analysis of inflammatory cells in synovial fluid after index anterior cruciate ligament reconstruction surgery (2016)
  • Author(s): Kaori Nakamura, Kunikazu Tsuji, Hiroki Katagiri, Makiko Inoue, Miyoko Ojima, Ichiro Sekiya, Takeshi Muneta
  • Organizer: Osteoarthritis Research Society International
  • Place of Presentation: Amsterdam Netherlands
  • Year and Date: 2016-03-31
  • Int'l Joint Research
• [Presentation] 滑膜由来間葉系幹細胞を特徴付ける表面抗原の網羅的解析 (2016)
  • Author(s): 辻 邦和、尾島美代子、小田邉浩二、堀江雅史、古賀英之、関矢一郎、宗田 大
  • Organizer: 軟骨代謝学会
  • Place of Presentation: 広島県広島市、広島大学応仁会館
  • Year and Date: 2016-02-19
• [Presentation] 滑膜間葉系幹細胞の増殖におけるPDGFシグナルの細胞内伝達経路の解析 (2015)
  • Author(s): 金民大、辻邦和、関矢一郎、大川淳、宗田大
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 富山県富山市、富山国際会議場
  • Year and Date: 2015-10-22
• [Presentation] 滑膜由来間葉系幹細胞を特徴付ける表面抗原の網羅的解析 (2015)
  • Author(s): 辻 邦和、尾島美代子、小田邉浩二、堀江雅史、古賀英之、関矢一郎、宗田 大
  • Organizer: 日本運動器移植、再生医学研究会
  • Place of Presentation: 山口県宇部市、ANAクラウンプラザホテル
  • Year and Date: 2015-09-25
• [Presentation] 細胞剥離法の差異が滑膜由来間葉系幹細胞の表面抗原解析の結果に及ぼす影響 (2015)
  • Author(s): 尾島美代子、辻邦和、小田邉浩二、 堀江雅史、古賀英之、 関矢一郎、宗田 大
  • Organizer: 日本運動器移植、再生医学研究会
  • Place of Presentation: 山口県宇部市、ANAクラウンプラザホテル
  • Year and Date: 2015-09-25