Models of collective migration that integrate single-cell polarity and mechanics

项目摘要/摘要 集体细胞迁移在伤口愈合、形态发生、原肠形成以及病理过程中都是至关重要的。 流程。这种集体运动源于单个细胞的生物化学极化的协调。 这种协调的一些生物学细节已经被识别出来--许多不同类型的细胞整合在一起 通过钙粘附素从细胞-细胞接触中获得信息，以重新极化Rho GTP酶活性。这些生物化学 这些事件会引起一些刻板印象的反应，比如接触运动抑制(CIL)，细胞会重新极化并爬行 远离接触。在识别细胞中的分子参与者之间，我们的理解存在着关键的差距- 细胞相互作用，并能够预测细胞-细胞相互作用的变化如何推动 上皮层或侵入的细胞流。Camley小组的一个长期目标是开发计算机 集体细胞迁移的物理模型来弥补这一差距。该项目通过构建模型来实现这一目标 用真实的几何、力学和细胞-细胞信号来研究集体细胞迁移： 1.确定细胞几何形状对细胞-细胞相互作用的影响，如接触运动抑制 在二维衬底上执行在迁移细胞的碰撞中测试细胞-细胞相互作用的分析， 从而允许具有宽板状脂蛋白的细胞之间发生碰撞。然而，在体内，细胞与细胞之间的相互作用发生在 由三维细胞外基质、机械连接和相邻细胞建立的上下文， 我们都知道它们能改变运动能力。细胞如何可靠地集成高度可变的细胞-细胞接触 联系区域和持续时间以协调他们的运动？我们将开发模型来描述 细胞与细胞碰撞上的细胞和矩阵几何。这将包括最近关于细胞-细胞碰撞的实验 我们的合作者在其中发现传统的运动接触抑制几乎是不存在的。 2.了解肌球蛋白活性、fl功能和机械转导如何调节细胞-细胞破裂事件 无论是正常组织还是病变组织，细胞的侵入都可以通过从更大的组织中分离出来的细胞来发生。这是一个 集体入侵的关键部分。是什么控制了细胞-细胞破裂的关键步骤？我们假设这些 罕见的事件依赖于fl在细胞-细胞连接处肌球蛋白等马达蛋白水平上的作用。我们会 开发模型来描述这种链入侵，传播如何依赖于细胞运动，以及 细胞来感知施加在连接处的力。我们将开发工具来推断 细胞-细胞连接处的张力和细胞运动直接来自实验数据。这些数据将用于来自 合作者研究受控微fl亚几何结构中的入侵。此外，我们还将开展模型研究 从一条链上断裂的簇的大小如何取决于链的几何形状。 这些模型共同提供了从细胞-细胞碰撞的物理和分子方面到大规模的联系 集体移徙，并将推动今后集体移徙和发展方面的问题。

Project Summary/Abstract Collective cell migration is critical in wound healing, morphogenesis, gastrulation, as well as in pathological processes. This collective motion arises from coordination of the biochemical polarization of individual cells. Some of the biological details of this coordination have been identified – many different cell types integrate information from cell-cell contact through cadherins in order to repolarize Rho GTPase activity. These biochemical events drive stereotyped reactions like contact inhibition of locomotion (CIL), where cells repolarize and crawl away from contact. There is a critical gap in our understanding between identifying molecular players in cell- cell interactions and being able to predict how changes in cell-cell interactions drive collective migration of an epithelial layer or an invading stream of cells. A long-term goal of the Camley group is developing computational physical models of collective cell migration to bridge this gap. This project addresses that goal by building models of collective cell migration with realistic geometry, mechanics and cell-cell signaling to study: 1. Determining the effect of cell geometry on cell-cell interactions like contact inhibition of locomotion Assays to test cell-cell interactions in collisions of migrating cells are performed on two-dimensional substrates, allowing collisions to occur between cells with broad lamellipodia. However, in vivo, cell-cell interactions occur in a context established by three-dimensional extracellular matrix, mechanical confinement, and neighboring cells, which are all known to alter motility. How can cells reliably integrate cell-cell contacts with highly variable contact areas and durations to coordinate their motion? We will develop models to describe the effect of cell and matrix geometry on cell-cell collisions. This will include recent experiments on cell-cell collisions on suspended fibers, in which our collaborators found traditional contact inhibition of locomotion is near-absent. 2. Understanding how myosin activity fluctuations and mechanotransduction regulate cell-cell rupture events Invasion of cells in both normal and diseased tissue can occur by cells breaking off from a larger group. This is a key part of collective invasion. What controls the critical step of cell-cell rupture? We hypothesize that these rare events are dependent on fluctuations in the level of motor proteins like myosin at cell-cell junctions. We will develop models to describe this strand invasion, how dissemination depends on cell motility, and the ability of cells to sense the forces exerted on junctions. We will develop tools to infer models of feedbacks between the tension at the cell-cell junction and cell motility directly from experimental data. These will be used on data from collaborators studying invasion in controlled microfluidic geometries. In addition, we will develop models studying how the size of clusters breaking from a strand depend on the strand geometry. Together, these models provide links from physical and molecular aspects of cell-cell collisions to large-scale collective migration, and will drive future questions in collective migration and development.