| Project/Area Number |
16K21508
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Orthopaedic surgery
General medical chemistry
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| Research Institution | Kindai University |
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Principal Investigator |
ONODERA Yuta 近畿大学, 医学部附属病院, 助手 (30510911)
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| Research Collaborator |
TERAMURA Takeshi
TAKEHARA Toshiyuki
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 間葉系幹細胞 / TAK1 / 細胞増殖 / Hippo pathway / 髄腔内移植 / 移植 / MSC / Stemness / 幹細胞 / ストレス / ES細胞 / 再生医療 / プロテオミクス |
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| Outline of Final Research Achievements |
Bone marrow-derived mesenchymal stem cells (BMMSCs) are multipotent stem cells
capable of differentiation into a variety of cell types, proliferation, and production of clinically useful secretory factors. However, the molecular network underlying BMMSC proliferation remains poorly understood. Here, we showed that Tgfβ-activated kinase (Tak1) is a critical molecule that regulates the activation of cell cycling and that Tak1 inhibition leads to quiescence in BMMSCs. Mechanistically, Tak1 was phosphorylated by growth factor stimulations, binding with Yap1/Taz, and supported their nuclear localization through stabilization of Yap1/Taz in proliferating BMMSCs. Furthermore, we also demonstrated that the cell-cycle synchronization in quiescence by Tak1 inhibition significantly improved engraftment after intra-bone marrow cell transplantation of BMMSCs. This study may suggest a novel central pathway controlling the BMMSC proliferation and useful pre-treatment for cell transplantation.
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| Academic Significance and Societal Importance of the Research Achievements |
TAK1の活性阻害あるいは発現抑制は単独でMSCの増殖をほぼ完全に抑制するという観察結果を得た。ES細胞でTAK1をノックアウトし、in vivo、in vitroでMSCを誘導すると、MSCは形成されるが増殖力が著しく低下した。さらに興味深いことに、MSCで見られるTAK1依存性細胞増殖は、既知の分子経路とは独立して生じていた。このことから、TAK1はMSCの増殖に必須の分子であり、未知の分子経路によって増殖制御を行っていること、さらに、その制御はMSCを用いた新たな再生医療技術の提案につながると考えた。
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