Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Cell Syst. 2022 Jul 20;13(7):514-529.e10. doi: 10.1016/j.cels.2022.05.005. Epub 2022 Jun 8.
Navigation through a dense, physically confining extracellular matrix is common in invasive cell spread and tissue reorganization but is still poorly understood. Here, we show that this migration is mediated by cyclic changes in the activity of a small GTPase RhoA, which is dependent on the oscillatory changes in the activity and abundance of the RhoA guanine nucleotide exchange factor, GEF-H1, and triggered by a persistent increase in the intracellular Ca levels. We show that the molecular clock driving these cyclic changes is mediated by two coupled negative feedback loops, dependent on the microtubule dynamics, with a frequency that can be experimentally modulated based on a predictive mathematical model. We further demonstrate that an increasing frequency of the clock translates into a faster cell migration within physically confining spaces. This work lays the foundation for a better understanding of the molecular mechanisms dynamically driving cell migration in complex environments.
在细胞浸润和组织重构过程中，细胞经常需要穿越物理上受限的细胞外基质，但目前这一过程的分子机制仍不清楚。本研究表明，这种迁移是由小 GTP 酶 RhoA 的活性循环变化介导的，该变化依赖于 RhoA 鸟嘌呤核苷酸交换因子 GEF-H1 的活性和丰度的振荡变化，并由细胞内 Ca 水平的持续增加触发。我们发现，驱动这些循环变化的分子钟是由两个偶联的负反馈环介导的，其依赖于微管动力学，并且可以根据预测的数学模型进行实验调节。我们进一步证明，时钟频率的增加会导致细胞在物理受限空间中的迁移速度加快。本工作为深入理解复杂环境中动态驱动细胞迁移的分子机制奠定了基础。
