Revealing forces driving collective cell migration

摘要 这项研究计划融合了生物学、物理学和应用数学的概念，以产生 将细胞力量的产生和传递与迁移联系起来的新理解。一个主要的焦点领域 是集体细胞迁移，它是组织发育和进展的基本过程 疾病的威胁。这项研究计划的长期愿景是应用实验知情的计算 预测生化扰动将如何影响集体迁徙的模型。这样的模型将 能够设计控制集体迁移的方法，这将导致重要的治疗 对人类健康的影响，如慢性伤口的愈合，减缓癌细胞的入侵，以及 所需尺寸和形状的工程组织。 实现这种建模能力需要生物物理方法，因为运动的结果是 细胞响应生物信号产生的物理力，并通过 细胞层。虽然存在测量力的方法，但常用的方法通常是 对于集体运动的基于物理的模型或对生物化学信号的研究来说，没有任何信息 产生力量。因此，需要改进现有的方法并开发新的方法 量化作用力，同时连接到基于物理的模型和基础 生物学。这个为期5年的Mira奖的目标是推进在两个国家中量化细胞力量的方法 体外和体内系统，并应用这些方法来建立框架，从而能够对 集体细胞迁移中生化信号、力和运动之间的关系。 为了实现这些目标，这项研究将采取两种平行的方法。有一种方法会有所改进 基于目前可用的测量每个细胞产生的力的实验方法，包括 这些力在空间和时间上的变化。另一种方法将开发一种新的方法来 通过将数据科学的方法与物理学相结合来量化细胞作用力。重要的是，这一新的 方法学将能够仅从细胞的图像中推断细胞力，这意味着它可以应用于 复杂的细胞培养系统，甚至在体内。这两种方法将被用来研究集体 通过围绕两个互补框架组织研究来进行迁移：第一个框架将研究集体 运动通过关注与相邻细胞之间的局部重排相关的力； 第二，将决定运动如何在多细胞群体中协调。这两个人加在一起 框架将提供一种方法，将关于集体迁徙的观察组织成一个整体 理解，这将暗示潜在的生物学机制，并提供必要的步骤 朝着实现能够预测集体的实验知情的计算模型前进 在伤口愈合、癌症侵袭和组织工程等应用中的迁移。

ABSTRACT This research program integrates concepts of biology, physics, and applied mathematics to produce new understanding connecting cell force generation and transmission to migration. A major area of focus is collective cell migration, which underlies essential processes in development of tissues and progression of disease. The long-term vision of this research program is to apply experiment-informed computational models to predict how biochemical perturbations will affect the collective migration. Such models would enable design of methods to control the collective migration, which would lead to therapies with important impacts on human health, such as healing of chronic wounds, slowing invasion of cancer cells, and engineering tissues of desired size and shape. Achieving this modeling capability requires a biophysical approach, because the motion results from physical forces that are produced by the cells in response to biological signaling and transmitted across the cell layer. Although there exist methods to measure the forces, the common methods used are often uninformative for physics-based models of collective motion or for studies of the biochemical signaling that produces the forces. Thus, there is a need to improve upon current methods and to develop new methods to quantify forces while simultaneously connecting to both the physics-based models and the underlying biology. The goals for this 5-year MIRA award are to advance methods in quantifying cell forces in both in vitro and in vivo systems and to apply those methods to build frameworks that enable modeling the relationships between biochemical signaling, forces, and motion in collective cell migration. To accomplish these goals, the research will take two parallel approaches. One approach will improve upon currently available experimental methods to measure forces produced by each cell, including the variation of those forces in space and time. The other approach will develop a new methodology for quantifying cell forces by integrating methods of data science with physics. Importantly, this new methodology will be able to infer cell forces from only images of the cells, meaning it can be applied in complicated cell culture systems and even in vivo. The two approaches will be used to study the collective migration by organizing the research around two complementary frameworks: the first will study collective motion by focusing on the forces associated with local rearrangements between neighboring cells; the second will determine how motion is coordinated across multicellular groups. Together, these two frameworks will provide a means to organize observations about collective migration into a holistic understanding, which will hint at the underlying biological mechanisms and provide an essential step forward towards achieving experiment-informed computational models that can predict the collective migration in applications such as wound healing, cancer invasion, and tissue engineering.