CAREER: Predictive Multiscale Modeling of Cell Migration through Pores between Endothelial Cells

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This Faculty Early Career Development (CAREER) award will support research that will study the cell migration through pores between endothelial cells using computer simulations. It is motivated by a fascinating and crucial process happening in our body every moment: a cell squeezes through pores much smaller than itself. For example, red blood cells around 8 μm, frequently squeeze through endothelial pores around 0.5 μm in our spleens. This is their regular ‘physical fitness test’, which destroys aged cells and diseased cells in malaria and blood disorders. Another example is the neutrophil, the most abundant white blood cell, which exits the circulation to fight infections in the tissues by squeezing through endothelial pores in the blood vessel walls. In cancer, circulating tumor cells also squeeze through these pores to metastasize in distant organs, which is the major contributor to cancer mortality. To squeeze through such narrow pores, all these cells have to experience extreme mechanical deformation. Slight changes of molecular structures in the cell would have significant consequence on the cell’s survival. In this project, advanced computer simulations will be applied to predict how different components of the cell affect its ability to pass through small pores. This research will also be complemented by educational and outreach programs based on curriculum development, hands-on construction of tensegrity structures, and a cell squeezing demonstrator to inspire K-12 students to pursue STEM careers. The research goal is to reveal the biomechanics and mechanobiology of transendothelial migration (TEM) of cells by multiscale modeling and its integration with experimental data. Although extensive experiments have been conducted to study TEM of cells, achieving a quantitative understanding has proven challenging without the aid of mathematical modeling. Unfortunately, there are limited predictive mathematical models of TEM due to its complex and multiscale nature. To address this challenge, the research will adopt a multiscale modeling approach and integrate experimental data to investigate TEM of three cell types: red blood cells, neutrophils, and tumor cells. Specifically, the research objectives include: (i) study TEM of mature and immature red blood cells during mechanical filtration in spleens; (ii) study TEM of neutrophils during inflammation response in lung capillary beds; (iii) study TEM of a tumor cell nucleus during cancer metastasis in distant organs. This project will advance our fundamental understanding of TEM and contribute valuable insights into a wide range of biomedical problems such as biomechanics and mechanobiology of cells.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.