标题： 轴突硬质趋性的多尺度力学 显示英文标题

标题： The multiscale mechanics of axon durotaxis

摘要： 在神经发育过程中，神经元轴突通过细胞外环境导航，受到各种线索的引导以与远端靶细胞建立连接。 除了其他因素外，轴突轨迹受环境刚度异质性的影响，这一过程称为 durotaxis，即通过基底刚度梯度进行引导。 在这里，我们开发了一个三尺度模型来描述轴突的 durotaxis。 在分子尺度上，我们表征了轴突生长锥细胞骨架之间的机械相互作用，这种相互作用基于依赖于基底刚度的分子离合器型相互作用。 在生长锥尺度上，我们将这种关系进行空间整合，以获得整个生长锥产生的牵引力模型。 最后，在细胞尺度上，我们将轴突建模为在粘附基底上生长的形态弹性纤维，并受到 durotactic 生长锥牵引力的作用。 首先，该模型预测，根据局部基底刚度，轴突可能表现出正向或负向的 durotaxis，并且我们证明这一关键特性意味着基底域中存在优选刚度的吸引区域。 其次，我们表明轴突在不同刚度区域之间的界面处会表现出反射和折射行为，这是一种基本过程，可能用于轴突的偏转。 最后，我们在一种生物学场景中测试了我们的模型，其中 durotaxis 之前已被确定为体内可能的引导机制。 总体而言，这项工作提供了一个通用的机械理论，用于探索轴突机械迁移和引导中的复杂效应。 显示英文摘要

摘要： During neurodevelopment, neuronal axons navigate through the extracellular environment, guided by various cues to establish connections with distant target cells. Among other factors, axon trajectories are influenced by heterogeneities in environmental stiffness, a process known as durotaxis, the guidance by substrate stiffness gradients. Here, we develop a three-scale model for axonal durotaxis. At the molecular scale, we characterise the mechanical interaction between the axonal growth cone cytoskeleton, based on molecular-clutch-type interactions dependent on substrate stiffness. At the growth cone scale, we spatially integrate this relationship to obtain a model for the traction generated by the entire growth cone. Finally, at the cell scale, we model the axon as a morphoelastic filament growing on an adhesive substrate, and subject to durotactic growth cone traction. Firstly, the model predicts that, depending on the local substrate stiffness, axons may exhibit positive or negative durotaxis, and we show that this key property entails the existence of attractive zones of preferential stiffness in the substrate domain. Second, we show that axons will exhibit reflective and refractive behaviour across interface between regions of different stiffness, a basic process which may serve in the deflection of axons. Lastly, we test our model in a biological scenario wherein durotaxis was previously identified as a possible guidance mechanism in vivo. Overall, this work provides a general mechanistic theory for exploring complex effects in axonal mechanotaxis and guidance in general.