A Combined Theoretical and Experimental Approach to Study Collective Cell Migration

研究集体细胞迁移的理论与实验相结合的方法

• 批准号: 1707637
• 负责人: Wouter-Jan Rappel
• 金额: $ 45万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1707637&HistoricalAwards=false
• 关键词: Combined; Theoretical; Experimental; Approach; Study

Cell motility plays a critical role in many biological and medical processes, including wound healing and morphogenesis. In most cases, cells do not move in isolation but move in groups. This collective motion is a process that is not yet well understood. In particular, it is not clear how cells that move within a group communicate and how cell-cell interaction and intracellular communication result in asymmetric, polarized cells. To tackle these questions using in vivo experiments is challenging since these experiments are hard to visualize and manipulate. In vitro experiments that follow large sheets of cells are slightly less difficult to visualize and probe but their results are not always easy to interpret, and are thus not ideal to determine the fundamental mechanisms of cell-cell interactions. To build a physics-based model for collective migration is also challenging, not only because the precise cell-cell interactions and intra-cellular mechanisms are unclear but also because the physical properties of cells, including membrane tension and rigidity, and cell morphology changes are difficult to implement. In this project the PI will overcome these challenges using an approach that combines theoretical and experimental investigations. He will formulate an efficient physics-based model that can incorporate the physical properties of deformable cells. The general framework of this model should be applicable to a wide variety of cell motility problems. He will also carry out careful and quantitative experiments. The proposed theoretical and experimental research will lead to deeper and fundamental insights into the mechanisms and processes involved in collective cell migration. The results will have direct relevance to many biological processes, including embryogenesis and wound healing. The PI anticipates that the theoretical and computational models developed as part of the proposal will be applicable to a wide range of multi-cellular processes and will have broad implications for biological modeling. In addition, the experiments should shed light on how cells interact when they collide, and how small groups of cells coordinate their motion. The PI will include the training of high school, undergraduates, and graduate students who will be directly involved in the proposed research. He will recruit talented underrepresented minorities through the on-going outreach efforts and programs of the Department of Physics and the Division of Physical Sciences and will offer two Research Experiences for Undergraduates internships. These students will be integrated into the lab and taught how to design, carry out, and interpret experiments and simulations. The goal is to attract diverse students to a career in the biophysical sciences. Furthermore, the PI will extend his existing collaboration with the Preuss Charter School, a top local high school that accepts students only from disadvantaged families. He will offer three internships to interested students, who can participate in all aspects of the research. Finally, the results of the project will be broadly disseminated to the academic community through publications, conferences and workshops.The PI's experimental approach consists of first studying how a collision between a pair of cells affects their motion and polarity. He will then extend these investigations to a small group of cells and will determine how these cells move in a collective fashion. The experiments and simulations will be carried out on micro-patterned surfaces which enables the PI to carefully control cell polarization and will allow him to quantify not only cell motion but also the spatio-temporal dynamics of intra-cellular communication. By comparing the experimental and theoretical results on cell collisions the PI will be able to determine cell-cell interaction mechanisms and parameters. He will then simulate collective cell migration and generate predictions that can be experimentally verified, resulting in a two-way dialogue between experiments and modeling. Specifically, he aims to: 1) Develop a computational framework that is able to model multiple deformable cells, physical cell membrane properties and different cell polarization mechanisms, and apply it to cell-cell collisions and collective motion of groups containing a small number of cells, and 2) Perform experiments using eukaryotic cells confined to micro-patterned surfaces that quantify cell-cell collisions and collective cell migration using confocal microscopy.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.

细胞运动在许多生物和医学过程中起着关键作用，包括伤口愈合和形态发生。在大多数情况下，细胞不是孤立地移动，而是成群地移动。这种集体运动是一个尚未被很好理解的过程。特别是，尚不清楚在组内移动的细胞如何进行通信，以及细胞间相互作用和细胞内通信如何导致不对称的极化细胞。使用体内实验来解决这些问题是具有挑战性的，因为这些实验很难可视化和操作。在体外实验中，跟随大片细胞的可视化和探测的难度稍低，但它们的结果并不总是容易解释，因此对于确定细胞-细胞相互作用的基本机制并不理想。建立一个基于物理学的集体迁移模型也具有挑战性，不仅因为精确的细胞间相互作用和细胞内机制尚不清楚，而且因为细胞的物理特性，包括膜张力和刚度，以及细胞形态变化难以实现。在这个项目中，PI将使用理论和实验研究相结合的方法来克服这些挑战。他将制定一个有效的基于物理的模型，可以结合可变形细胞的物理特性。这个模型的一般框架应该适用于各种各样的细胞运动问题。他还将进行细致的定量实验。所提出的理论和实验研究将导致对集体细胞迁移所涉及的机制和过程的更深入和根本的见解。这些结果将与许多生物过程直接相关，包括胚胎发生和伤口愈合。PI预计，作为提案的一部分开发的理论和计算模型将适用于广泛的多细胞过程，并将对生物建模产生广泛的影响。此外，这些实验应该揭示细胞碰撞时如何相互作用，以及小群细胞如何协调运动。PI将包括对高中生、本科生和研究生的培训，他们将直接参与拟议的研究。他将通过物理系和物理科学系正在进行的外联工作和计划招募有才华的代表性不足的少数民族，并将为本科生实习提供两个研究经验。这些学生将被整合到实验室，并学习如何设计，执行和解释实验和模拟。其目标是吸引不同的学生在生物物理科学的职业生涯。此外，PI将扩大与普鲁斯特许学校的现有合作，普鲁斯特许学校是当地一所顶级高中，只接受来自弱势家庭的学生。他将为感兴趣的学生提供三个实习机会，他们可以参与研究的各个方面。最后，该项目的成果将通过出版物、会议和研讨会广泛传播给学术界。PI的实验方法包括首先研究一对细胞之间的碰撞如何影响它们的运动和极性。然后，他将这些研究扩展到一小群细胞，并确定这些细胞如何以集体的方式移动。实验和模拟将在微图案化表面上进行，这使得PI能够仔细控制细胞极化，并使他不仅能够量化细胞运动，还能够量化细胞内通信的时空动态。通过比较细胞碰撞的实验和理论结果，PI将能够确定细胞-细胞相互作用机制和参数。然后，他将模拟集体细胞迁移，并生成可以通过实验验证的预测，从而实现实验和建模之间的双向对话。具体而言，他的目标是：1）开发一个能够模拟多个可变形细胞、物理细胞膜特性和不同细胞极化机制的计算框架，并将其应用于细胞-细胞碰撞和包含少量细胞的群体的集体运动，和2）使用限制在微图案表面的真核细胞进行实验，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Cell dispersal by localized degradation of a chemoattractant

通过化学引诱剂的局部降解实现细胞分散

• DOI: 10.1073/pnas.2008126118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Karmakar, Richa;Tyree, Timothy;Gomer, Richard H.;Rappel, Wouter-Jan
• 通讯作者: Rappel, Wouter-Jan

Cell motility dependence on adhesive wetting

• DOI: 10.1039/c8sm01832d
• 发表时间: 2019-03-07
• 期刊: SOFT MATTER
• 影响因子: 3.4
• 作者: Cao, Yuansheng;Karmakar, Richa;Rappel, Wouter-Jan
• 通讯作者: Rappel, Wouter-Jan

A minimal computational model for three-dimensional cell migration

• DOI: 10.1098/rsif.2019.0619
• 发表时间: 2019-12-01
• 期刊: JOURNAL OF THE ROYAL SOCIETY INTERFACE
• 影响因子: 3.9
• 作者: Cao, Yuansheng;Ghabache, Elisabeth;Rappel, Wouter-Jan
• 通讯作者: Rappel, Wouter-Jan

Cellular memory in eukaryotic chemotaxis depends on the background chemoattractant concentration

真核趋化中的细胞记忆取决于背景趋化剂浓度

• DOI: 10.1103/physreve.103.012402
• 发表时间: 2021
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Karmakar, Richa;Tang, Man-Ho;Yue, Haicen;Lombardo, Daniel;Karanam, Aravind;Camley, Brian A.;Groisman, Alex;Rappel, Wouter-Jan
• 通讯作者: Rappel, Wouter-Jan

Novel micropatterning technique reveals dependence of cell-substrate adhesion and migration of social amoebas on parental strain, development, and fluorescent markers

• DOI: 10.1371/journal.pone.0236171
• 发表时间: 2020-07-23
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Karmakar, Richa;Schich, Christoph;Tarantola, Marco
• 通讯作者: Tarantola, Marco