CAREER: Impacts of Intracellular and Extracellular Hydraulic Environments on Mammalian Cell Migration in Confined Spaces

This Faculty Early Career Development (CAREER) award will study how mammalian cell migration in confined space is influenced by the hydraulic environment both inside and outside the cell. Most of the current knowledge on the fluid dynamics in mammalian cell motility has been developed by studying fluid motion alone, or fluid interaction with a single type of structure. This limitation does not consider how the interaction of the fluid and structure affects cell behavior. This project will use mathematical modeling to decipher these coupled effects in confined cell migration. This project is expected to reveal new mechanisms of how hydraulics can actively facilitate confined cell migration. The results will open new avenues of research in the synergistic effect of fluid in biophysical processes such as immune response, wound healing, tissue regeneration, and cancer metastasis. The theoretical strategies are expected to advance modeling techniques in broader areas that involve multi-component coupling and foster creative designs for bio-inspired, water-based systems. Additionally, this project will enhance science and engineering education via developing an interdisciplinary course on cell mechanics in a partially flipped-classroom approach, nurturing future biophysicists through establishing a scaffolded undergraduate research program on the mathematical modeling of cell mechanics, and promoting K-12 interdisciplinary education through outreach programs targeting underrepresented students. The specific objectives of this project are as follows: (1) identify how the velocity of a migrating cell in a confined channel is affected by the presence of an additional cell at the front, (2) determine the condition when cells utilize unsynchronized nucleus-cell migration mode within confined spaces and quantify the associated energy efficiency, and (3) elucidate the dual role of the nucleus when cells deform into confined spaces from open spaces. Physiology- and continuum mechanics-based mathematical models will be developed to study the objectives. The models will target a few cell type-dependent features such as membrane protein expression levels and at the same time be as generic as possible to inform typical features of confined cell migration. The model results and prediction will be theoretically and experimentally evaluated. The outcomes are projected to have a positive impact by advancing the knowledge of the active roles of hydraulics in confined cell migration and the techniques of modeling strategies. 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.