Polarity signaling within and between cells analyzed in a 1D model of collective cell migration

在集体细胞迁移的一维模型中分析细胞内和细胞间的极性信号传导

• 批准号: RGPIN-2018-05831
• 负责人: Hayer, Arnold
• 金额: $ 2.26万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745738
• 关键词: Polarity; signaling; within; between; cells

Animal tissues are composed of large numbers of cells that together determine tissue shape and function. Collective behavior of cells in tissues is only possible when individual cells coordinate their behavior with their neighbors, by integrating signals that they receive from them or from their environment. During collective cell migration, individual cells employ their autonomous migration machinery for locomotion, while they are coupled to their neighbors through adhesive cell-cell contacts. Collective cell guidance therefore requires that adjacent cells coordinate their motility and polarity systems through intercellular communication. Despite the known importance of collective cell migration during development, tissue repair, and disease, fundamental aspects of how collective cell guidance is achieved remain unclear. A detailed understanding of the mechanisms mediating intercellular communication requires quantitative measurements of relevant structural and signaling parameters both in autonomously and collectively migrating cells. In this discovery research program, we will follow a novel strategy at the interface between biology, engineering, and physics, combining fluorescence-based biosensor measurements in live cells with microfabrication and computational image analyses. Micropatterned substrates with defined geometries will force otherwise heterogeneously behaving cells into predicable migration behaviors. Spatiotemporal patterns of multiple biosensor signals recorded individually can then be aligned to precise behavioral landmarks and their relationship to each other determined. In Aim 1, we will study autonomous signaling in individually migrating cells. We will spatiotemporally map patterns of signaling activities in unpolarized cells, in cells migrating on linear tracks, and during defined migration events, e.g. turning or repolarization. In Aim 2, we will use a simplified model of collective cell migration, where cells migrate collectively as trains on linear or circular micropatterned tracks. We will investigate how interactions between cells inform and modify autonomous signaling activities to achieve collective migration. This research program will establish relationships between critical signaling components and morphological changes, and create a new level of understanding of the complex mechanisms that govern autonomous and collective cell migration. By investigating how the signaling activities required for autonomous and collective cell migration are regulated in time and space, we aim to identify mechanisms of intercellular communication mediating collective cell behavior. Moreover, the proposed research will provide an excellent training opportunity for trainees interested in using cutting-edge technology that links physical approaches to studying fundamental aspects of collective cell behavior.

动物组织由大量细胞组成，这些细胞共同决定组织的形状和功能。只有当单个细胞通过整合它们从它们或从环境中接收的信号来协调它们与邻居的行为时，组织中细胞的集体行为才是可能的。在集体细胞迁移过程中，单个细胞利用其自主的迁移机制进行移动，同时它们通过粘连的细胞-细胞接触与相邻细胞相连。因此，集体细胞指导需要相邻细胞通过细胞间通信来协调它们的运动性和极性系统。尽管已知在发育、组织修复和疾病期间集体细胞迁移的重要性，但集体细胞指导如何实现的基本方面仍然不清楚。要详细了解调节细胞间通讯的机制，需要对自主和集体迁移细胞中的相关结构和信号参数进行定量测量。在这个发现研究计划中，我们将在生物学、工程学和物理学之间遵循一种新的策略，将活细胞中基于荧光的生物传感器测量与显微制造和计算图像分析相结合。具有特定几何形状的微图案化衬底将迫使原本表现不同的细胞进入可预测的迁移行为。然后，可以将单独记录的多个生物传感器信号的时空模式与精确的行为标志对准，并确定它们彼此之间的关系。在目标1中，我们将研究单个迁移细胞中的自主信号。我们将在时空上映射未极化细胞中、在线性轨道上迁移的细胞中以及在特定迁移事件期间的信号活动模式，例如转向或复极化。在目标2中，我们将使用一个简化的集体细胞迁移模型，在该模型中，细胞作为直线或环形微图案轨道上的列车集体迁移。我们将研究细胞之间的相互作用如何通知和修改自主信号活动，以实现集体迁移。这项研究计划将建立关键信号成分和形态变化之间的关系，并建立一个新的水平，以了解管理自主和集体细胞迁移的复杂机制。通过研究自主和集体细胞迁移所需的信号活动是如何在时间和空间上调节的，我们的目的是确定细胞间通讯调节集体细胞行为的机制。此外，拟议的研究将为对使用尖端技术感兴趣的受训者提供一个极好的培训机会，该技术将物理方法与研究集体细胞行为的基本方面联系起来。