Department of Biomedical Engineering, Peking University, Beijing 100871, PR China.
J Biomech. 2012 Jan 3;45(1):116-22. doi: 10.1016/j.jbiomech.2011.09.013. Epub 2011 Oct 20.
Cell adhesions are modulated by the interactions between cells and their surroundings, among which substrate stiffness plays an important role in mediating cellular behaviors and functions. Little is known, however, about the inherent mechanism of how nascent adhesion nucleation, as the precursor of focal adhesions, is regulated by substrate stiffness. This paper presents a microscopic model to imitate integrin clustering kinetics, where integrin diffusion, activation on elastic substrates, receptor-ligand binding and association dynamics are fully considered. Particularly, the contribution of substrate compliance to the activation energy is analyzed, leading to a description of mechanical energy barrier for stretching a substrate-bound integrin molecule from bent to extended conformations. A series of Monte Carlo simulations for integrin clustering dynamics are performed with varied substrate Young's moduli, which demonstrates that more integrins are clustered on stiffer substrates once they begin to assemble over a rigidity threshold, indicating the responsiveness of adhesion nucleation to substrate elasticity, which is in reasonable agreement with results reported previously. Also, these simulations show that the sensitivity of integrin clustering to substrate stiffness is mediated by chemical affinity between receptor-ligand pairs and that between integrins cross-linked by adapter proteins, as well as integrin density on cell membranes. The investigation offers a fascinating insight into the inherent mechanism of mechanosensing concerning integrin-mediated cell-matrix initial adhesions.
细胞黏附受到细胞与其周围环境相互作用的调节，其中基质硬度在调节细胞行为和功能方面起着重要作用。然而，关于起始黏附核形成的内在机制（焦点黏附的前体）如何受基质硬度调节，人们知之甚少。本文提出了一个微观模型来模拟整合素簇集动力学，其中充分考虑了整合素扩散、在弹性基质上的激活、受体-配体结合和缔合动力学。特别地，分析了基底柔顺性对激活能的贡献，从而描述了从弯曲到伸展构象拉伸基底结合整合素分子的机械能势垒。通过改变基质杨氏模量，对整合素簇集动力学进行了一系列蒙特卡罗模拟，结果表明，一旦整合素在刚性阈值以上开始组装，更多的整合素就会聚集在更硬的基质上，这表明黏附核形成对基质弹性的响应性，这与先前报道的结果基本一致。此外，这些模拟表明，整合素簇集对基质刚度的敏感性受受体-配体对之间以及由衔接蛋白交联的整合素之间的化学亲和力以及细胞膜上整合素密度的调节。该研究为研究整合素介导的细胞基质初始黏附的机械感觉内在机制提供了一个迷人的视角。
