ERI: Multi-Scale Modeling of Cell-Matrix Mechanical Interactions in Endothelial Cell Network Assembly

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This Engineering Research Initiation (ERI) award will support research about how mammalian cells organize into functional multicellular structures. Specifically, how cells organize through physical cues will be revealed. The focus will be on self-organized cell networks. These networks are known to occur prior to blood vessel formation. They require specific properties to successfully transport nutrients and oxygen. Tissue can be engineered in synthetic environments if the conditions are right. Those conditions include a combination of cells, materials, and chemical factors. Engineering these tissues by mechanical manipulations of the cell network can also have effects. Better understanding these mechanisms means that damaged tissues can ultimately be restored and replaced. The results of this research will contribute to both scientific understanding and national health. The multidisciplinary research approach will be combined with educational activities. These activities will introduce students to quantitative approaches in the life sciences. This project will also contribute to the recruitment, retention, and training of students in science and engineering fields in the underserved Central Valley region of California. The research will use mathematical modeling and agent-based computation to identify the multicellular structures that result from intercellular interactions mediated by the elastic deformations of the extracellular substrate. A cell can exert contractile traction forces to deform or restructure its material environment. The modeling will combine individual cell motility with cell-cell mechanical interactions through their mutual deformations of the substrate. The substrate will be modeled at multiple scales as a linear elastic continuum as well as a discrete, fibrous medium. The model cell networks obtained in simulation will be analyzed quantitatively to obtain crucial metrics related to transport functions such as the number of junctions, branches and loops, and their space coverage. These quantitative measures will predict how the cell network structure and function depend on substrate mechanical properties. These results will be compared with analysis of available experimental data on vascular cell networks on soft substrates. The modeling developed during this project can be extended in the future to describe the self-assembly of other cell types in other culture geometries including three-dimensional assemblies.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.