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

项目概要/摘要 集体细胞迁移对于伤口愈合、形态发生、原肠胚形成以及病理学至关重要 流程。这种集体运动源于单个细胞生化极化的协调。 这种协调的一些生物学细节已经被确定——许多不同的细胞类型整合在一起 通过钙粘蛋白获得细胞与细胞接触的信息，以重新极化 Rho GTP 酶活性。这些生化 事件会驱动刻板反应，例如接触运动抑制 (CIL)，细胞会重新极化并爬行 远离接触。我们对识别细胞中的分子参与者之间的理解存在着重大差距 细胞相互作用并能够预测细胞间相互作用的变化如何驱动细胞的集体迁移 上皮层或入侵的细胞流。 Camley 小组的长期目标是开发计算 集体细胞迁移的物理模型可以弥补这一差距。该项目通过构建模型来实现这一目标 通过真实的几何形状、力学和细胞信号传导来研究集体细胞迁移： 1. 确定细胞几何形状对细胞间相互作用（如运动的接触抑制）的影响 在二维基质上进行迁移细胞碰撞中细胞间相互作用的测试， 允许具有宽片状伪足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、机械限制和邻近细胞建立的环境， 众所周知，这些都会改变运动能力。细胞如何可靠地整合具有高度可变性的细胞间接触 协调其运动的接触面积和持续时间？我们将开发模型来描述效果 细胞与细胞碰撞时的细胞和矩阵几何形状。这将包括最近关于细胞与细胞碰撞的实验 悬浮纤维，我们的合作者发现传统的接触运动抑制几乎不存在。 2. 了解肌球蛋白活性波动和力转导如何调节细胞间破裂事件 从较大群体中分裂出来的细胞可能会侵袭正常组织和患病组织中的细胞。这是一个 集体入侵的关键部分。是什么控制着细胞与细胞破裂的关键步骤？我们假设这些 罕见事件取决于细胞与细胞连接处肌球蛋白等运动蛋白水平的波动。我们会 开发模型来描述这种链的入侵、传播如何依赖于细胞运动以及 细胞感知施加在连接处的力。我们将开发工具来推断之间的反馈模型 细胞与细胞连接处的张力和细胞运动直接来自实验数据。这些将用于数据 合作者研究受控微流体几何形状的入侵。此外，我们将开发模型研究 从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与细胞碰撞的物理和分子方面到大规模 集体移民，并将推动未来集体移民和发展的问题。

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.