Mechanisms of rigidity-dependent differentiation of mesenchymal stem cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02471
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tohoku University
• Principal Investigator: Mizuno Kensaku 東北大学, 生命科学研究科, 名誉教授 (70128396)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 間葉系幹細胞 / 脂肪細胞分化 / アクチン骨格 / Rho / RhoGEF / 力覚応答

Outline of Final Research Achievements

Our research aimed to elucidate the molecular mechanism of substrate stiffness-dependent differentiation of mesenchymal stem cells (MSCs) through actin cytoskeletal remodeling. RhoGEFs, activators of Rho small GTPases, contribute to each function of actin remodeling that has diversified during evolution in higher organisms. We comprehensively searched for the RhoGEFs that are involved in adipocyte differentiation of MSCs using RNA interference method, and identified 7 and 14 RhoGEFs as contributing to the promotion and suppression of adipocyte differentiation, respectively. Ten of the 14 RhoGEFs that inhibit adipocyte differentiation are RhoA-targeting GEFs, six of which were reported to be involved in mechanical stress responses. These results suggest that these RhoGEFs regulate MSC differentiation in a manner dependent on substrate stiffness.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によって、アクチン骨格の再構築を介して間葉系幹細胞(MSC)の脂肪細胞分化を促進及び抑制するRhoGEFを多数同定することに成功した。MSCは、成体から単離することが可能な多能性の幹細胞であり、再生医療の有望なシーズであるが、その分化誘導や未分化状態を維持して培養することが未だ困難である。今回の成果は、MSCが外部の力学的環境に応じて分化方向を決定する新たな分子機構の発見につながるとともに、MSCを効率良く任意の細胞へ分化させる方法や多分化能を維持して大量に培養する技術の開発につながることが期待される。