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，这些细胞共同决定了组织的形状和功能。组织中细胞的集体行为只有当单个细胞通过整合从邻居或环境中接收到的信号来协调它们的行为时才有可能。在集体细胞迁移过程中，单个细胞利用其自主迁移机制进行运动，同时它们通过黏附细胞-细胞接触与邻近细胞结合。因此，集体细胞引导需要相邻细胞通过细胞间通讯协调它们的运动和极性系统。尽管已知集体细胞迁移在发育、组织修复和疾病中的重要性，但集体细胞引导如何实现的基本方面仍不清楚。要详细了解介导细胞间通讯的机制，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。在这个发现研究项目中，我们将遵循生物学、工程学和物理学之间的新策略，将活细胞中基于荧光的生物传感器测量与微加工和计算图像分析相结合。具有定义几何形状的微图案基底将迫使其他异质性行为的细胞进入可预测的迁移行为。单独记录的多个生物传感器信号的时空模式可以与精确的行为标志对齐，并确定它们彼此之间的关系。在Aim 1中，我们将研究单个迁移细胞中的自主信号传导。我们将绘制非极化细胞、沿线性轨迹迁移的细胞以及在定义的迁移事件（如转向或复极化）期间的信号活动的时空图谱。在目标2中，我们将使用集体细胞迁移的简化模型，其中细胞在线性或圆形微图案轨道上作为火车集体迁移。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。该研究计划将建立关键信号成分和形态变化之间的关系，并对控制自主和集体细胞迁移的复杂机制产生新的理解。通过研究自主和集体细胞迁移所需的信号活动如何在时间和空间上受到调节，我们旨在确定细胞间通讯介导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学员提供极好的培训机会，这些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。