Cao Xuan, Lin Yuan, Driscoll Tristian P, Franco-Barraza Janusz, Cukierman Edna, Mauck Robert L, Shenoy Vivek B
Department of Materials Science and Engineering, School of Engineering and Applied Science, The University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Mechanical Engineering, The University of Hong Kong, Hong Kong SAR, China.
Biophys J. 2015 Nov 3;109(9):1807-17. doi: 10.1016/j.bpj.2015.08.048.
In this work, a chemomechanical model describing the growth dynamics of cell-matrix adhesion structures (i.e., focal adhesions (FAs)) is developed. We show that there are three regimes for FA evolution depending on their size. Specifically, nascent adhesions with initial lengths below a critical value that are yet to engage in actin fibers will dissolve, whereas bigger ones will grow into mature FAs with a steady state size. In adhesions where growth surpasses the steady state size, disassembly will occur until their sizes are reduced to the equilibrium state. This finding arises from the fact that polymerization of adhesion proteins is force-dependent. Under actomyosin contraction, individual integrin bonds within small FAs (i.e., nascent adhesions or focal complexes) must transmit higher loads while the phenomenon of stress concentration occurs at the edge of large adhesion patches. As such, an effective stiffness of the FA-extracellular matrix complex that is either too small or too large will be relatively low, resulting in a limited actomyosin pulling force developed at the edge that is insufficient to prevent disassembly. Furthermore, it is found that a stiffer extracellular matrix and/or nucleus, as well as a stronger chemomechanical feedback, will induce larger adhesions along with a higher level of contraction force. Interestingly, switching the extracellular side from an elastic half-space, corresponding to some widely used in vitro gel substrates, to a one-dimensional fiber (as in the case of cells anchoring to a fibrous scaffold in vivo) does not qualitative change these conclusions. Our model predictions are in good agreement with a variety of experimental observations obtained in this study as well as those reported in the literature. Furthermore, this new model, to our knowledge, provides a framework with which to understand how both intracellular and extracellular perturbations lead to changes in adhesion structure number and size.
在这项工作中，我们建立了一个化学机械模型来描述细胞-基质粘附结构（即粘着斑（FAs））的生长动力学。我们发现，根据粘着斑的大小，其演化存在三种状态。具体而言，初始长度低于临界值且尚未与肌动蛋白纤维结合的新生粘着斑会溶解，而较大的粘着斑会生长为具有稳态大小的成熟粘着斑。当粘着斑的生长超过稳态大小时，就会发生分解，直到其大小减小到平衡状态。这一发现源于粘附蛋白的聚合是力依赖的这一事实。在肌动球蛋白收缩作用下，小粘着斑（即新生粘着斑或粘着斑复合体）内的单个整合素键必须传递更高的负荷，而在大粘附斑边缘会出现应力集中现象。因此，粘着斑-细胞外基质复合体的有效刚度过小或过大时，其相对较低，导致在边缘产生的肌动球蛋白拉力有限，不足以防止分解。此外，研究发现，更硬的细胞外基质和/或细胞核，以及更强的化学机械反馈，会诱导形成更大的粘着斑以及更高水平的收缩力。有趣的是，将细胞外一侧从对应于一些广泛使用的体外凝胶基质的弹性半空间切换到一维纤维（如细胞在体内锚定到纤维支架的情况）并不会定性地改变这些结论。我们的模型预测与本研究中获得的各种实验观察结果以及文献中报道的结果高度一致。此外，据我们所知，这个新模型提供了一个框架，用以理解细胞内和细胞外的扰动如何导致粘附结构数量和大小的变化。
