Bailey Alexander M, Thorne Bryan C, Peirce Shayn M
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Ann Biomed Eng. 2007 Jun;35(6):916-36. doi: 10.1007/s10439-007-9266-1. Epub 2007 Apr 10.
Leukocyte trafficking through the microcirculation and into tissues is central in angiogenesis, inflammation, and the immune response. Although the literature is rich with mechanistic detail describing molecular mediators of these processes, integration of signaling events and cell behaviors within a unified spatial and temporal framework at the multi-cell tissue-level is needed to achieve a fuller understanding. We have developed a novel computational framework that combines agent-based modeling (ABM) with a network flow analysis to study monocyte homing. A microvascular network architecture derived from mouse muscle was incorporated into the ABM. Each individual cell was represented by an individual agent in the simulation. The network flow model calculates hemodynamic parameters (blood flow rates, fluid shear stress, and hydrostatic pressures) throughout the simulated microvascular network. These are incorporated into the ABM to affect monocyte transit through the network and chemokine/cytokine concentrations. In turn, simulated monocytes respond to their local mechanical and biochemical environments and make behavioral decisions based on a rule set derived from independent literature. Simulated cell behaviors give rise to emergent leukocyte rolling, adhesion, and extravasation. Molecular knockout simulations were performed to validate the model, and predictions of monocyte adhesion, rolling, and extravasation show good agreement with the independently published corresponding mouse studies.
白细胞通过微循环进入组织在血管生成、炎症和免疫反应中起着核心作用。尽管文献中有丰富的关于这些过程分子介质的机制细节描述，但在多细胞组织水平的统一时空框架内整合信号事件和细胞行为，才能更全面地理解。我们开发了一种新颖的计算框架，将基于主体的建模（ABM）与网络流分析相结合来研究单核细胞归巢。源自小鼠肌肉的微血管网络架构被纳入ABM。在模拟中，每个单独的细胞由一个单独的主体表示。网络流模型计算整个模拟微血管网络中的血流动力学参数（血流速度、流体剪切应力和静水压力）。这些参数被纳入ABM以影响单核细胞在网络中的转运以及趋化因子/细胞因子浓度。反过来，模拟的单核细胞对其局部机械和生化环境做出反应，并根据从独立文献得出的规则集做出行为决策。模拟的细胞行为导致出现白细胞滚动、黏附和外渗。进行了分子敲除模拟以验证该模型，单核细胞黏附、滚动和外渗的预测结果与独立发表的相应小鼠研究结果显示出良好的一致性。
