Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
Materials Science and Engineering, Arizona State University, Tempe, Arizona 85287, USA.
Phys Rev E. 2019 Oct;100(4-1):043303. doi: 10.1103/PhysRevE.100.043303.
Cell migration in fibrous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response, and cancer progression. During migration, individual cells can generate active pulling forces via actomyosin contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Here, we develop a computational model for two-dimensional cell migration regulated by cell-ECM micromechanical coupling. Our model explicitly takes into account a variety of cellular-level processes, including focal adhesion formation and disassembly, active traction force generation and cell locomotion due to actin filament contraction, transmission and propagation of tensile forces in the ECM, as well as the resulting ECM remodeling. We validate our model by accurately reproducing single-cell dynamics of MCF-10A breast cancer cells migrating on collagen gels and show that the durotaxis and contact guidance effects naturally arise as a consequence of the cell-ECM micromechanical interactions considered in the model. Moreover, our model predicts strongly correlated multicellular migration dynamics, which are resulted from the ECM-mediated mechanical coupling among the migrating cell and are subsequently verified in in vitro experiments using MCF-10A cells. Our computational model provides a robust tool to investigate emergent collective dynamics of multicellular systems in complex in vivo microenvironment and can be utilized to design in vitro microenvironments to guide collective behaviors and self-organization of cells.
细胞在纤维细胞外基质（ECM）中的迁移对于许多生理和病理过程至关重要，例如组织再生、免疫反应和癌症进展。在迁移过程中，单个细胞可以通过肌动球蛋白收缩产生主动的拉力，这些力通过粘着斑复合物传递到 ECM 纤维上，重塑 ECM，并最终传播到系统中的其他细胞并被其感知。ECM 的微观结构和物理特性也会显著影响细胞迁移，例如趋硬性和接触引导。在这里，我们开发了一个受细胞-ECM 微观力学耦合调控的二维细胞迁移计算模型。我们的模型明确考虑了各种细胞水平的过程，包括粘着斑的形成和解体、肌动蛋白丝收缩引起的主动牵引力的产生和细胞运动、ECM 中张力的传递和传播，以及由此产生的 ECM 重塑。我们通过准确再现 MCF-10A 乳腺癌细胞在胶原凝胶上的单细胞动力学来验证我们的模型，并表明趋硬性和接触引导效应是模型中考虑的细胞-ECM 微观力学相互作用的自然结果。此外，我们的模型还预测了强烈相关的多细胞迁移动力学，这是由于迁移细胞之间的 ECM 介导的力学耦合所致，随后在使用 MCF-10A 细胞的体外实验中得到了验证。我们的计算模型为研究复杂体内微环境中多细胞系统的新兴集体动力学提供了一个强大的工具，并可用于设计体外微环境以指导细胞的集体行为和自组织。
