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A Combined Theoretical and Experimental Approach to Study Collective Cell Migration: University of California-San Diego

Wouter-Jan Rappel

[email protected]

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.<br/><br/>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.<br/><br/>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.

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