The Biophysics of Collective Cell Locomotion

单个受精的卵细胞要形成胚胎，有许多中间步骤，包括重复细胞分裂和器官在正确位置的发育。但这一过程及其监管的细节尚未浮出水面。例如，在海鞘中，一对细胞是这种有机体心脏的起点。海鞘是一个比人类胚胎更简单的系统，但有许多共同之处。这些细胞必须在来自胚胎内部的提示的指导下，从它们的起源移动到心脏的未来位置。当配对的细胞移动时，它们必须将其他细胞推出到达目的地的路径，同时不会失去彼此的联系。尽管对参与器官形成的细胞组的协调运动的观察研究促进了对胚胎发育和相关先天性疾病的了解，但该项目将通过使用数学建模和计算机模拟来梳理这一过程的许多方面，从而加深理解。该项目将包括为细胞边界和内部动力学之间的机械相互作用开发新的计算机模拟方案，为启动集体迁移所需的生物化学建立新的模型，为有效地求解变形、运动几何中的方程提供新的方法，并将其扩展到全三维区域。调查人员将利用该项目的跨学科性质来招聘和培训本科生和研究生。对生物体集体运动的研究导致了指导生物发现的重要数学模型的建立。这个项目的一个显著特点是，多体相互作用是通过机械力化学键与细胞的生物化学和生物力学以一种未知的方式相互作用而实现的。我们重点研究了重要的模式生物--海鞘的心脏发育早期的两个细胞的集体迁移。最初，这两个细胞是难以区分的，但在某些时候，它们建立了领导者和追随者的角色，并以不同的形态移动，挤过了可变形的组织。实验表明，作为一对凝聚的细胞而不是单个细胞移动是有优势的，然而，目前还不清楚为什么两个细胞不会彼此减速。这些观察导致了以下问题：细胞内机制是如何整合起来的，以产生作为一个有凝聚力的群体的运动性？为什么两个细胞一起移动比单独移动更快？两个细胞系统在极化和启动迁移方面比单个细胞更好吗？数学建模可以帮助实验回答这些问题，但模型方程的数值解将需要开发新的计算方法，能够模拟复杂演变几何结构中的耦合力学、传输和化学反应方程。与实验实验室的合作将导致发现一组最小但充分的相互作用，这些相互作用是凝聚细胞组的机械和生化组织的基础。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

For a single fertilized egg cell to form into an embryo, there are many intermediate steps, including repeated cell division and development of organs in the correct location. But the details of this process and its regulation have yet to emerge. For example, in the sea squirt -- a simpler system than the human embryo but one that shares a lot of commonalities -- a pair of cells is the starting point of the heart of this organism. These cells must move from their origin to the future location of the heart guided by cues from inside the embryo. As the paired cells move, they must push other cells out of their path to reach their destination, all while not losing contact with each other. Although observational studies of the coordinated movement of groups of cells involved in organ formation advance knowledge of embryonic development and associated congenital conditions, this project will deepen understanding by employing mathematical modeling and computer simulations to tease out the many facets of this process. The project will involve developing new computer simulation schemes for the mechanical interactions between cell boundary and interior dynamics, new models for the biochemistry needed to initiate collective migration, new methods for efficiently solving equations in deforming, moving geometries, and extensions to full three-dimensional domains. The investigators will use the interdisciplinary nature of the project to recruit and train undergraduate and graduate students. The study of collective locomotion of organisms has led to important mathematical models that have guided biological discovery. A distinguishing feature of this project is that the multi-body interaction is achieved through mechanochemical bonds that interact with the cell's biochemistry and biomechanics in an unknown way. We focus on the collective migration of two cells in the early stages of heart development of the sea squirt Ciona intestinalis, an important model organism. Initially, these two cells are indistinguishable, yet at some point they establish leader and follower roles and move with distinct morphologies, squeezing through deformable tissues. Experiments show there is an advantage to move as a cohesive pair rather than a single cell, however, it is unclear why two cells do not slow each other down. These observations lead to the following questions: How are intracellular mechanics integrated to give rise to motility as a cohesive group? Why can two cells move faster together than alone? Is the two-cell system better at polarization and initiating migration than an individual cell? Mathematical modeling can aid experiments in answering these questions, but numerical solutions of the model equations will require development of novel computational methods that will be able to simulate coupled mechanical, transport, and chemical reaction equations in complex evolving geometries. Collaboration with an experimental lab will result in the discovery of a set of minimal yet sufficient interactions underlying the mechanical and biochemical organization of a cohesive cell group.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.