Essential role of TAK1 in the maintenance of Stemness of the Mesenchymal stem cells.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K21508
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery; General medical chemistry
• Research Institution: Kindai University
• Principal Investigator: ONODERA Yuta 近畿大学, 医学部附属病院, 助手 (30510911)
• Research Collaborator: TERAMURA Takeshi ; TAKEHARA Toshiyuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 間葉系幹細胞 / TAK1 / 細胞増殖 / Hippo pathway / 髄腔内移植

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.

Free Research Field

幹細胞生物学

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。