Orthopedic Research Laboratory, University of Zurich, Forchstrasse 340, Balgrist, CH-8008 Zurich, Switzerland.
Integr Biol (Camb). 2012 May;4(5):508-21. doi: 10.1039/c2ib00158f. Epub 2012 Mar 27.
We present a novel approach to modeling cell spreading, and use it to reveal a potentially central mechanism regulating focal adhesion maturation in various cell phenotypes. Actin bundles that span neighboring focal complexes at the lamellipodium-lamellum interface were assumed to be loaded by intracellular forces in proportion to bundle length. We hypothesized that the length of an actin bundle (with the corresponding accumulated force at its adhesions) may thus regulate adhesion maturation to ensure cell mechanical stability and morphological integrity. We developed a model to test this hypothesis, implementing a "top-down" approach to simplify certain cellular processes while explicitly incorporating complexity of other key subcellular mechanisms. Filopodial and lamellipodial activities were treated as modular processes with functional spatiotemporal interactions coordinated by rules regarding focal adhesion turnover and actin bundle dynamics. This theoretical framework was able to robustly predict temporal evolution of cell area and cytoskeletal organization as reported from a wide range of cell spreading experiments using micropatterned substrates. We conclude that a geometric/temporal modeling framework can capture the key functional aspects of the rapid spreading phase and resultant cytoskeletal complexity. Hence the model is used to reveal mechanistic insight into basic cell behavior essential for spreading. It demonstrates that actin bundles spanning nascent focal adhesions such that they are aligned to the leading edge may accumulate centripetal endogenous forces along their length, and could thus trigger focal adhesion maturation in a force-length dependent fashion. We suggest that this mechanism could be a central "integrating" factor that effectively coordinates force-mediated adhesion maturation at the lamellipodium-lamellum interface.
我们提出了一种新的细胞扩展建模方法，并利用该方法揭示了一种潜在的核心机制，该机制调节了各种细胞表型中的焦点黏附成熟。在边缘-板层界面处跨越相邻焦点复合物的肌动蛋白束被假设为受到细胞内力的加载，其与束的长度成比例。我们假设，肌动蛋白束的长度（及其在黏附物处的相应累积力）可能会调节黏附成熟，以确保细胞的机械稳定性和形态完整性。我们开发了一个模型来检验这个假设，采用“自上而下”的方法来简化某些细胞过程，同时明确纳入其他关键亚细胞机制的复杂性。丝状伪足和片状伪足的活动被视为具有功能时空相互作用的模块化过程，这些相互作用由关于焦点黏附物周转率和肌动蛋白束动力学的规则来协调。这个理论框架能够稳健地预测细胞面积和细胞骨架组织的时间演变，正如广泛使用微图案化基底的细胞扩展实验所报道的那样。我们得出结论，一个几何/时间建模框架可以捕捉快速扩展阶段和由此产生的细胞骨架复杂性的关键功能方面。因此，该模型被用于揭示对扩展至关重要的基本细胞行为的机制见解。它表明，跨越新形成的焦点黏附物的肌动蛋白束，使得它们与前缘对齐，可能会沿着其长度积累向心的内源性力，并以力-长度依赖的方式触发焦点黏附物的成熟。我们认为，这种机制可能是一种有效的核心“整合”因素，有效地协调了在边缘-板层界面处的力介导的黏附物成熟。
