整合素信号分子Kindlin2 在生物力学影响间充质干细胞分化中的调控作用

Mesenchymal Stem Cells (MSC) are a group of adult stem cells broadly present in the bone marrow stroma. They are capable of multilineage differentiation and are able to be induced to form osteoblasts, chondrocytes, myocytes and vascular endothelium. Hence, MSC has the potential to be used for therapy in a variety of diseases and has been widely studied in clinical research. Evidence shows that biophysical signals are essential regulators for MSC differentiation. However, how mechanical signals are transduced within the cell remains poorly understood. Our preliminary results show that Kindlin2, an adaptor protein critical in mediating Integrin signaling, is highly expressed in MSC and forms a complex with MLCK, which is an essential regulator of Myosin activity. Given that Myosin activity is crucial for matrix elasticity-directed MSC fate specification, we propose that the binding of Kindlin2 to MLCK may play an essential role in regulating mechanotransduction-mediated MSC differentiation. We propose a series of experiments, including the use of substrates with different stiffness for MSC culture to mimick different matrix elasticity. The aim of this project is to understand the physiological roles of Kindlin2-MLCK interaction, especially in the maintenance of Myosin activity in MSC, and in the control of MSC fate decisions induced by biophysical signals.

间充质干细胞（MSC）是一类来源广泛的成体干细胞，在体内和体外培养的条件下能够被诱导分化形成骨骼，肌肉，血管内皮等组织的细胞，在临床应用领域具有巨大的研究价值。近年来许多研究证据显示，生物力学信号是诱导MSC分化的重要调控因素。然而，对于生物力学信号如何在细胞内传递的具体机制仍未被阐述清楚。我们前期的工作发现，整合素信号分子Kindlin2高表达于体外培养的MSC，并且能够与调控肌球蛋白（Myosin）活性的激酶MLCK分子相结合。由于Myosin分子是细胞内传递机械力信号的重要调节因子，我们猜测Kindlin2-MLCK的结合对机械力诱导MSC的定向分化具有关键的调控作用。本项目将以不同软硬度的基底培养MSC，模拟体内环境所受到的不同弹性力，同时，系统探索Kindlin2-MLCK相互作用的生理学意义，尤其是对于Myosin活性的维持，以及在机械力诱导MSC分化过程中所扮演的角色。