细胞变形和运动是胚胎发育、组织形貌发生和肿瘤入侵等的基础，涉及细胞动力学、极化分子的扩散和复杂的力感知和力传导信号通路，对其进行力化学耦合研究有助于理解生理和病理过程背后的力生物学机制。本文结合理论建模和细胞力学实验表征，研究了力学微环境在调控单、多细胞变形和运动中所扮演的重要角色。 首先，建立了活性柔链模型刻画多细胞系统中出现的复杂的形状变化行为，发现了描述细胞形状随密度变化的临界本征形状因子，在群体拥堵时细胞的形状因子依赖于细胞的本征形状。通过考察细胞间相互作用力，阐释了细胞间粘附对细胞运动能力、细胞纵横比和弯折度的影响，探讨了细胞牵引力和应力纤维在细胞变形和解拥堵转变行为中的关键作用。 其次，基于活性柔链模型中的单细胞框架，建立了新的耦合基底刚度的细胞多尺度力化学理论模拟细胞对基底刚度的响应。发现存在基底刚度阈值激活细胞极化，而Cdc42的有效扩散可以调控极化模式，并且影响细胞运动速度。进而揭示了在牵引力增强效应下，存在最优基底刚度使得细胞迁移最快。 此外，引入细胞间力感知通路，研究了单细胞和群体细胞趋硬迁移行为的力生物学机制。探讨了基底软硬界面、刚度梯度、初始位置刚度、细胞单层尺寸、细胞间粘附对细胞趋硬行为的影响，复现了多个典型实验现象，发现细胞单层边缘产生的牵引力差异是触发群体细胞趋硬迁移的驱动力。 最后，开发了多细胞单层界面应力显微镜方法，研究了单层界面处的牵引力和界面应力分布。揭示了单层融合和上皮单层抵抗癌细胞入侵过程中，单层界面处的牵引力和界面应力的时空演化规律。 本文的研究有助于理解细胞迁移的力生物学机制，可为疤痕愈合、组织再生工程以及肿瘤疗法等提供理论基础。
Cell deformation and migration are the basis of many significant physiological and pathological processes, such as embryonic development, tissue morphogenesis, and tumor invasion, which involve cell dynamics, diffusion of polarized molecules, and complex force sensing and transduction signaling pathways. Studying the mechano-chemical coupling in cell deformation and migration may help to understand the mechanobiological mechanisms underlying these physiological and pathological processes. In this dissertation, we investigate the important role of mechanical micoenvironment in regulating deformation and migration of single and collective cells, by combining theoretical modelling and experimental characterization. Firstly, the active flexible chain model is established to describe the complex deformation behavior occurring in multicellular systems. Based on this model, a critical intrinsic shape factor is found to describe how cell shape changes with density. It shows that the cell shape in jamming phase is dependent on the intrinsic shape of the cells. By incorporating cell–cell interactions, the effects of cell–cell adhesion on cell motility, cell aspect ratio, and tortuosity are revealed. The important roles of traction force and stress fibers in cell deformation and unjamming transition behaviors are studied further. Secondly, based on the single-cell framework in the proposed active flexible chain model, a new multiscale mechanochemical theory coupled with substrate stiffness is established to simulate the cellular response to substrate stiffness. There exists a critical polarization stiffness to activate cell polarization. In addition, the effective diffusion coefficient of Cdc42 can regulate the polarization modes and affect the cell migration speed subsequently. An optimal migration stiffness that enables fastest cell migration with force reinforcement mechanism has been found. Thirdly, we investigate the mechanobiological mechanism of single and collective cell durotaxis by introducing an intercellular force sensing pathway. The effects of the soft–hard interface, substrate stiffness gradient, the stiffness of initial cell position, cell monolayer size and cell–cell adhesion on cellular durotaxis are investigated. Many typical experimental phenomena are reproduced. It is found that the difference in traction force generated by the soft and hard edges of the cell monolayer drives collective cell durotaxis. Finally, a multicellular monolayer interfacial stress microscopy is developed to investigate the traction force and interfacial stress distribution. The spatiotemporal evolution of traction force and interfacial stress during monolayer fusion and epithelial monolayer against cancer monolayer invasion are revealed. This work is helpful to understand the mechanobiological mechanisms of cell migration, and can provide a theoretical basis for wound healing, tissue regeneration engineering, and tumor therapy.
