Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes
Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes
复制标题
DOI：
10.1073/pnas.1417257112
复制
发表时间：
2015-04-21
影响因子：
11.1
通讯作者：
Mogilner, Alex
中科院分区：
文献类型：
--
作者：
Barnhart, Erin;Lee, Kun-Chun;Mogilner, Alex
细胞是动态系统，能够自发地在稳定状态之间切换。其中一个明显的例子是鱼类上皮细胞的自发对称性破坏和运动性启动。尽管在这些细胞中控制稳态迁移的生化和机械机制已经被很好地描述，但对称性破坏背后的机制还不是很清楚。在这项工作中，我们结合了细胞-底物黏附强度和肌球蛋白活性的实验操作，牵引力测量和数学建模，建立了鱼类上皮角质细胞对称性破坏和运动启动的综合力学模型。我们的结果表明，黏附强度和肌球蛋白局部化的随机波动驱动未来细胞中肌动蛋白网络的流速超过临界阈值。超过这个阈值，高的肌动蛋白流速会导致粘连强度的非线性切换，局部地将粘连从抓取切换到滑动，并进一步加速预期细胞后部的肌动蛋白流动，导致后部收缩和运动启动。我们通过实验和模型模拟进一步证明，黏附强度和肌球蛋白活性的整体水平控制着静止状态的稳定性：对称性破缺的频率随着黏附强度的增加而减少，随着肌球蛋白收缩的增加而增加。因此，两种相反的机械力--伸缩性和细胞-底物粘附力--的相对强度决定了自发对称性破缺和运动性启动的可能性。
Cells are dynamic systems capable of spontaneously switching among stable states. One striking example of this is spontaneous symmetry breaking and motility initiation in fish epithelial keratocytes. Although the biochemical and mechanical mechanisms that control steady-state migration in these cells have been well characterized, the mechanisms underlying symmetry breaking are less well understood. In this work, we have combined experimental manipulations of cell-substrate adhesion strength and myosin activity, traction force measurements, and mathematical modeling to develop a comprehensive mechanical model for symmetry breaking and motility initiation in fish epithelial keratocytes. Our results suggest that stochastic fluctuations in adhesion strength and myosin localization drive actin network flow rates in the prospective cell rear above a critical threshold. Above this threshold, high actin flow rates induce a nonlinear switch in adhesion strength, locally switching adhesions from gripping to slipping and further accelerating actin flow in the prospective cell rear, resulting in rear retraction and motility initiation. We further show, both experimentally and with model simulations, that the global levels of adhesion strength and myosin activity control the stability of the stationary state: The frequency of symmetry breaking decreases with increasing adhesion strength and increases with increasing myosin contraction. Thus, the relative strengths of two opposing mechanical forces-contractility and cell-substrate adhesion-determine the likelihood of spontaneous symmetry breaking and motility initiation.