Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America.
PLoS Comput Biol. 2022 Aug 26;18(8):e1009937. doi: 10.1371/journal.pcbi.1009937. eCollection 2022 Aug.
The dynamic interplay between cell adhesion and protrusion is a critical determinant of many forms of cell motility. When modeling cell spreading on adhesive surfaces, traditional mathematical treatments often consider passive cell adhesion as the primary, if not exclusive, mechanistic driving force of this cellular motion. To better assess the contribution of active cytoskeletal protrusion to immune-cell spreading during phagocytosis, we here develop a computational framework that allows us to optionally investigate both purely adhesive spreading ("Brownian zipper hypothesis") as well as protrusion-dominated spreading ("protrusive zipper hypothesis"). We model the cell as an axisymmetric body of highly viscous fluid surrounded by a cortex with uniform surface tension and incorporate as potential driving forces of cell spreading an attractive stress due to receptor-ligand binding and an outward normal stress representing cytoskeletal protrusion, both acting on the cell boundary. We leverage various model predictions against the results of a directly related experimental companion study of human neutrophil phagocytic spreading on substrates coated with different densities of antibodies. We find that the concept of adhesion-driven spreading is incompatible with experimental results such as the independence of the cell-spreading speed on the density of immobilized antibodies. In contrast, the protrusive zipper model agrees well with experimental findings and, when adapted to simulate cell spreading on discrete adhesion sites, it also reproduces the observed positive correlation between antibody density and maximum cell-substrate contact area. Together, our integrative experimental/computational approach shows that phagocytic spreading is driven by cellular protrusion, and that the extent of spreading is limited by the density of adhesion sites.
细胞黏附与突起之间的动态相互作用是许多形式的细胞运动的关键决定因素。在模拟细胞在黏附表面上的扩展时，传统的数学处理方法通常将被动细胞黏附视为这种细胞运动的主要（如果不是唯一的）机械驱动力。为了更好地评估细胞骨架突起在免疫细胞吞噬过程中对细胞扩展的贡献，我们在此开发了一个计算框架，该框架允许我们选择性地研究纯黏附扩展（“布朗尼拉链假说”）和突起主导的扩展（“突起拉链假说”）。我们将细胞建模为一个轴对称的高粘性流体体，周围是一个具有均匀表面张力的皮质，并将由于受体-配体结合而产生的吸引力和代表细胞骨架突起的向外法向应力作为细胞扩展的潜在驱动力纳入其中，这两种力都作用于细胞边界。我们利用各种模型预测结果与人类中性粒细胞在涂有不同密度抗体的底物上吞噬扩展的直接相关实验对照研究的结果进行对比。我们发现，黏附驱动扩展的概念与实验结果（例如细胞扩展速度与固定化抗体密度无关）不兼容。相比之下，突起拉链模型与实验结果吻合得很好，当将其改编为模拟离散黏附位点上的细胞扩展时，它还再现了观察到的抗体密度与最大细胞-底物接触面积之间的正相关关系。总的来说，我们的综合实验/计算方法表明，吞噬扩展是由细胞突起驱动的，扩展的程度受黏附位点密度的限制。
