Dynamic Mechanisms of Cell Rigidity Sensing: Insights from a Computational Model of Actomyosin Networks

Cells modulate themselves in response to the surrounding environment like substrate elasticity, exhibiting structural reorganization driven by the contractility of cytoskeleton. The cytoskeleton is the scaffolding structure of eukaryotic cells, playing a central role in many mechanical and biological functions. It is composed of a network of actins, actin cross-linking proteins (ACPs), and molecular motors. The motors generate contractile forces by sliding couples of actin filaments in a polar fashion, and the contractile response of the cytoskeleton network is known to be modulated also by external stimuli, such as substrate stiffness. This implies an important role of actomyosin contractility in the cell mechano-sensing. However, how cells sense matrix stiffness via the contractility remains an open question. Here, we present a 3-D Brownian dynamics computational model of a cross-linked actin network including the dynamics of molecular motors and ACPs. The mechano-sensing properties of this active network are investigated by evaluating contraction and stress in response to different substrate stiffness. Results demonstrate two mechanisms that act to limit internal stress: (i) In stiff substrates, motors walk until they exert their maximum force, leading to a plateau stress that is independent of substrate stiffness, whereas (ii) in soft substrates, motors walk until they become blocked by other motors or ACPs, leading to submaximal stress levels. Therefore, this study provides new insights into the role of molecular motors in the contraction and rigidity sensing of cells.

细胞可响应包括基底弹性在内的周遭环境进行自身调控，并展现出由细胞骨架（Cytoskeleton）收缩力驱动的结构重排现象。细胞骨架是真核细胞的支架结构，在诸多机械与生物学功能中发挥核心作用，由肌动蛋白、肌动蛋白交联蛋白（ACPs）与分子马达构成的网络组成。这类分子马达通过以极性方式滑动成对的肌动蛋白丝产生收缩力，而细胞骨架网络的收缩响应同样会受基底刚度等外部刺激的调控，这表明肌动球蛋白（Actomyosin）收缩性在细胞机械传感中扮演着重要角色。然而，细胞如何通过收缩力感知基质刚度仍是一个尚未解决的科学问题。本文提出了一种包含分子马达与肌动蛋白交联蛋白动力学过程的交联肌动蛋白网络三维布朗动力学（Brownian Dynamics）计算模型。通过评估不同基底刚度下的收缩与应力情况，本研究对该活性网络的机械传感特性进行了探究。研究结果揭示了两种可限制内部应力的机制：（i）在刚性基底中，分子马达会持续运动直至达到最大施力水平，此时产生的平台应力与基底刚度无关；（ii）在软基底中，分子马达会在被其他马达或肌动蛋白交联蛋白阻断前停止运动，此时应力处于次最大水平。因此，本研究为阐明分子马达在细胞收缩与刚度感知中的作用提供了全新的视角。