Exploring the inhibitory effect of membrane tension on cell polarization

Cell polarization toward an attractant is influenced by both physical and chemical factors. Most existing mathematical models are based on reaction-diffusion systems and only focus on the chemical process occurring during cell polarization. However, membrane tension has been shown to act as a long-range inhibitor of cell polarization. Here, we present a cell polarization model incorporating the interplay between Rac GTPase, filamentous actin (F-actin), and cell membrane tension. We further test the predictions of this model by performing single cell measurements of the spontaneous polarization of cancer stem cells (CSCs) and non-stem cancer cells (NSCCs), as the former have lower cell membrane tension. Based on both our model and the experimental results, cell polarization is more sensitive to stimuli under low membrane tension, and high membrane tension improves the robustness and stability of cell polarization such that polarization persists under random perturbations. Furthermore, our simulations are the first to recapitulate the experimental results described by Houk et al., revealing that aspiration (elevation of tension) and release (reduction of tension) result in a decrease in and recovery of the activity of Rac-GTP, respectively, and that the relaxation of tension induces new polarity of the cell body when a cell with the pseudopod-neck-body morphology is severed.

细胞向趋化因子的极化过程同时受到物理与化学因素的共同调控。现有绝大多数数学模型均以反应扩散系统为基础，且仅聚焦于细胞极化过程中发生的化学过程。然而已有研究证实，细胞膜张力可作为细胞极化的长程抑制剂。本研究构建了一个整合Rac GTP酶（Rac GTPase）、丝状肌动蛋白（filamentous actin, F-actin）与细胞膜张力之间相互作用的细胞极化模型。鉴于癌症干细胞（cancer stem cells, CSCs）的细胞膜张力低于非干细胞性癌细胞（non-stem cancer cells, NSCCs），本研究通过对这两类细胞的自发极化行为开展单细胞测量，进一步验证了该模型的预测结果。结合模型与实验结果分析可知，在细胞膜张力较低的情况下，细胞极化对刺激信号更为敏感；而较高的细胞膜张力则可提升细胞极化的鲁棒性与稳定性，使极化过程在随机扰动下仍能维持。此外，本研究的模拟实验首次复现了Houk等人报道的实验结果：抽吸操作（即张力升高）与张力释放（即张力降低）可分别导致Rac-GTP活性的下降与恢复；而当具有伪足-颈部-胞体形态的细胞被切断时，张力松弛可诱导胞体产生新的极化方向。