2021 Fiscal Year Final Research Report

Transforming Growth Factor beta-Activated Kinase 1 Regulates Mesenchymal Stem Cell Proliferation Through Stabilization of Yap1/Taz Proteins

Research Project

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Project/Area Number	19K09562
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56020:Orthopedics-related
Research Institution	Kindai University
Principal Investigator	ONODERA Yuta 近畿大学, 大学病院, 助教 (30510911)
Co-Investigator(Kenkyū-buntansha)	寺村岳士近畿大学, 大学病院, 講師 (40460901) 竹原俊幸近畿大学, 大学病院, 助教 (60580561)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	間葉系幹細胞 / 細胞増殖 / 細胞移植 / Tak1 / Hippo Pathway
Outline of Final Research Achievements	BMMSCs are multipotent stem cells capable of differentiation into a variety of cell types, proliferation, and production of clinically useful secretory factors. These advantages make BMMSCs highly useful for cell transplantation therapy. However, the molecular network underlying BMMSC proliferation remains poorly understood. Here, we showed that Tak1 is a critical molecule that regulates the activation of cell cycling and that Tak1 inhibition leads to quiescence in BMMSCs both in vivo and in vitro.Tak1 was phosphorylated by growth factor stimulations, allowing it to bind and stabilize Yap1/Taz, which could then be localized to the nucleus. We also demonstrated that the quiescence induction by inhibiting Tak1 increased oxidized stress tolerance and improved BMMSC engraftment in intrabone marrow cell transplantation models. This study reveals a novel pathway controlling BMMSC proliferation and suggests a useful method to improve the therapeutic effect of BMMSC transplantation.
Free Research Field	幹細胞生物学
Academic Significance and Societal Importance of the Research Achievements	本研究の成果から、Tak1の制御がBMMSCの幹細胞性を維持する上で重要であることが解明された。Tak1はBMMSCの細胞周期の活性化に重要なキナーゼであり、Tak1の抑制が生体内と生体外の両方で細胞周期の静止状態を誘導した。Tak1は、さまざまな成長因子によって活性化される可能性があり、Yap1/Tazの安定化を通じてBMMSCの細胞周期を活性化する。また、BMMSCにおけるTak1阻害による細胞増殖の静止誘導は、細胞移植時のストレス耐性および生着結果を改善するものであった。したがってTak1は、BMMSCの自己複製に寄与するだけでなく、治療効果を改善するための重要な分子だと考えられる。