Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory), and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China.
School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China.
Biomech Model Mechanobiol. 2018 Dec;17(6):1611-1630. doi: 10.1007/s10237-018-1047-2. Epub 2018 Jul 2.
Directional neutrophil migration during human immune responses is a highly coordinated process regulated by both biochemical and biomechanical environments. In this paper, we developed an integrative mathematical model of neutrophil migration using a lattice Boltzmann-particle method built in-house to solve the moving boundary problem with spatiotemporal regulation of biochemical components. The mechanical features of the cell cortex are modeled by a series of spring-connected nodes representing discrete cell-substrate adhesive sites. The intracellular signaling cascades responsible for cytoskeletal remodeling [e.g., small GTPases, phosphoinositide-3-kinase (PI3K), and phosphatase and tensin homolog] are built based on our previous four-layered signaling model centered on the bidirectional molecular transport mechanism and implemented as reaction-diffusion equations. Focal adhesion dynamics are determined by force-dependent integrin-ligand binding kinetics and integrin recycling and are thus integrated with cell motion. Using numerical simulations, the model reproduces the major features of cell migration in response to uniform and gradient biochemical stimuli based on the quantitative spatiotemporal regulation of signaling molecules, which agree with experimental observations. The existence of multiple types of integrins with different binding kinetics could act as an adaptation mechanism for substrate stiffness. Moreover, cells can perform reversal, U-turn, or lock-on behaviors depending on the steepness of the reversal biochemical signals received. Finally, this model is also applied to predict the responses of mutants in which PTEN is overexpressed or disrupted.
在人类免疫反应中，定向中性粒细胞迁移是一个高度协调的过程，受到生化和生物力学环境的共同调节。在本文中，我们使用自主开发的格子玻尔兹曼-粒子方法构建了一个整合的中性粒细胞迁移数学模型，以解决具有时空生化成分调节的移动边界问题。细胞皮质的力学特征通过一系列弹簧连接的节点来建模，这些节点代表离散的细胞-基底附着点。负责细胞骨架重塑的细胞内信号级联[例如，小 GTP 酶、磷酸肌醇-3-激酶 (PI3K) 和磷酸酶和张力蛋白同系物]是基于我们之前的以双向分子运输机制为中心的四层信号模型构建的，并实现为反应-扩散方程。粘着斑动力学由力依赖性整合素-配体结合动力学和整合素循环决定，因此与细胞运动相结合。通过数值模拟，该模型根据信号分子的定量时空调节，再现了细胞对均匀和梯度生化刺激的主要迁移特征，这与实验观察结果一致。具有不同结合动力学的多种整合素的存在可以作为对基底硬度的适应机制。此外，根据所接收的逆转生化信号的陡峭程度，细胞可以表现出逆转、U 型转弯或锁定行为。最后，该模型还被应用于预测过表达或破坏 PTEN 的突变体的反应。
