3D Mechanical Modeling of Epithelial Stratification and Turnover

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Skin is a biological tissue composed of multiple components and cell types which work in concert to perform critical functions, such as creating a flexible barrier to the outside environment and healing wounds. To perform these functions, skin has multiple layers – a bottom layer composed of cells that can divide and transform into other cell types, and top layers of cells that rarely divide and have specialized shapes with specific tasks. Recent research hints that mechanical interactions between these cell types help keep the layers separate and regulate cell divisions, but there are few quantitative models to carefully test this hypothesis. This project will develop a new biophysical computational model for skin layers that accounts for mechanical interactions between cells. In collaboration with cell biology experiments, this research will link model parameters to the expression of specific biomolecules, such as adhesion molecules or components of the cell cytoskeleton. It will then make predictions for cell and tissue shapes, as well as the rates at which cells leave the bottom layer to renew the tissue over time. These predictions will be tested in experiments. Finally, it will test the hypothesis that cells sense mechanical signals transmitted through the tissue and consequently alter the production of adhesion and cytoskeletal molecules, resulting in a mechanical feedback loop that helps to correctly regulate tissue growth and prevent disease. The researchers will provide a publicly available simulation code for 3D epithelial tissues, engage students under-represented in STEM fields in research and professional development experiences, and disseminate lectures and computational exercises on modeling cell mechanics.The goal of this project is to make and test quantitative predictions for the mechanical response of self-renewing stratified epithelia, using mammalian skin as a model system. The project will develop a novel 3D computational model representing cell shapes and tissue layers within the epithelium, constrain the model with state-of-the-art experimental cell biology and mechanobiology measurements, and then test quantitative model predictions for global tissue behavior. The work focuses on two objectives. In Objective 1 the team will use a first-of-its kind layered 3D vertex model to study the properties of the barrier/interface between the basal and suprabasal layer in both wildtype and knockout stratified epithelia, testing the hypothesis that heterotypic interactions between the two cell types and the basement membrane generate an effective mechanical barrier, and isolating how specific proteins contribute to that barrier. In Objective 2 the team will extend the 3D vertex model to study dynamic motion of cells across the barrier to understand how cell division, cell death, adhesion changes, and active cell migration drive delamination (i.e., allow cells from the basal layer to move to the suprabasal layer). The hypothesis that specific, cell-autonomous processes inside delaminating cells work together, possibly via mechanosensitive feedback loops, with tissue-scale mechanical processes (such as cell-division-driven unjamming) to precisely regulate cross-layer motion will be tested.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.