MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands.
Dept. of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
PLoS One. 2021 Mar 18;16(3):e0248293. doi: 10.1371/journal.pone.0248293. eCollection 2021.
The distribution of signaling molecules following mechanical or chemical stimulation of a cell defines cell polarization, with regions of high active Cdc42 at the front and low active Cdc42 at the rear. As reaction-diffusion phenomena between signaling molecules, such as Rho GTPases, define the gradient dynamics, we hypothesize that the cell shape influences the maintenance of the "front-to-back" cell polarization patterns. We investigated the influence of cell shape on the Cdc42 patterns using an established computational polarization model. Our simulation results showed that not only cell shape but also Cdc42 and Rho-related (in)activation parameter values affected the distribution of active Cdc42. Despite an initial Cdc42 gradient, the in silico results showed that the maximal Cdc42 concentration shifts in the opposite direction, a phenomenon we propose to call "reverse polarization". Additional in silico analyses indicated that "reverse polarization" only occurred in a particular parameter value space that resulted in a balance between inactivation and activation of Rho GTPases. Future work should focus on a mathematical description of the underpinnings of reverse polarization, in combination with experimental validation using, for example, dedicated FRET-probes to spatiotemporally track Rho GTPase patterns in migrating cells. In summary, the findings of this study enhance our understanding of the role of cell shape in intracellular signaling.
细胞在受到机械或化学刺激后，信号分子的分布决定了细胞的极化状态，高活性的 Cdc42 集中在前端，低活性的 Cdc42 则集中在后端。由于信号分子（如 Rho GTPases）之间的反应扩散现象决定了梯度动力学，我们假设细胞形状会影响“前后”细胞极化模式的维持。我们使用已建立的计算极化模型研究了细胞形状对 Cdc42 模式的影响。我们的模拟结果表明，不仅细胞形状，而且 Cdc42 和 Rho 相关（失活）激活参数值都会影响活性 Cdc42 的分布。尽管存在初始的 Cdc42 梯度，但模拟结果表明，最大的 Cdc42 浓度会向相反的方向移动，我们将这种现象称为“反向极化”。进一步的模拟分析表明，“反向极化”仅在导致 Rho GTPases 失活和激活之间平衡的特定参数值空间中发生。未来的工作应集中在对反向极化基础的数学描述上，并结合使用例如专用的 FRET 探针来时空追踪迁移细胞中 Rho GTPase 模式的实验验证。总之，本研究的结果增强了我们对细胞形状在细胞内信号转导中的作用的理解。
