真核细胞运动接触抑制行为的力学-化学耦合模拟

Mechanical-chemical coupling simulation of contact inhibition of locomotion in eukaryotic cells

某些真核细胞可通过运动的接触抑制特性显著调控细胞散布、群体细胞迁移及癌细胞转移等生理、病理进程.本文基于“多层次”信号级联转导调控细胞定向迁移,考察细胞间接触调控细胞骨架重组的动力学过程,由此构建模拟运动细胞接触抑制行为的力学-化学耦合模型.细胞考虑为包含网格状微丝骨架的圆环结构,细胞接触引起微丝骨架全局应变及局部黏附共同调控Rho GTPase家族成员Rac及RhoA活性.整体数学模型由非线性反应-扩散方程组及平衡微分方程构成,对其采取自行发展LBM-D1Q3法数值求解.数值模拟通过改变FilGAP-FLNa与N-cadherin通路对细胞接触的反馈强度,重现了双细胞接触抑制实验观测现象.模拟表明,FilGAP对Rac发挥适当抑制作用有利于细胞维持理想极性,从而在N-cadherin调控下反转极性,展现出接触抑制行为;缺乏FilGAP抑制会使得细胞高度极化,此时N-cadherin调控作用不足以反转细胞已有极性,产生接触后绕行通过行为;缺乏N-cadherin调控作用会使得细胞在接触后无法反转极性,最终呈现静态黏附行为.上述模拟结果对认识细胞接触抑制信号对细胞迁移行为的影响提供了理论基础.

Contact inhibition of locomotion(CIL)drives various biological phenomena,including cell dispersion,collective cell migration,and cancer invasion.Based on our previously proposed cell migration model with multilayered signaling cascades,a mechanical-chemical coupling model for CIL was developed by further incorporating cell-cell contact-dependent signaling pathways to guide the cytoskeleton remodeling.The cell structure model incorporates a discrete actin filament network within a cycle.The entire mathematical model is composed of nonlinear diffusion-reaction equations coupled with forcebalance equations and solved numerically by the in-house built LBP-D1Q3 method.Numerical simulations indicated that the manifestation of distinct CIL behavior depends on the cooperation between Fil GAP-FLNa and N-cadherin signaling pathways in terms of Rho GTPase signaling.After achieving a suitable inhibitory effect of Fil GAP,the cells retain moderate polarity,which can be reversed in response to N-cadherin signaling,leading to normal CIL behavior.The lack of Fil GAP transforms the cells to a fully polarized state,which is difficult to reverse,thus leading to the“bypass”behavior.The lack of N-cadherin signaling prevents cells from repolarizing in response to cell-cell contact,leading to static cell-cell adhesion.These simulations provide a theoretical basis for understanding the effect of contact inhibition signaling on cell migration.