Integrative biophysical modeling for collective tissue mechanics

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Project Summary/Abstract Organ surfaces are covered with epithelial cells or endothelial cells, providing physical barriers for organs and bodies. Cells on these confluent layers often remain static and non-migratory. However, they can also undergo active structural rearrangements during basic physiological processes ranging across embryonic development, morphogenesis, repair, and remodeling. In each of these events, an epithelial collective necessarily undergoes a transition from a solid-like state which is quiescent and non-migratory to a fluid-like state which is dynamic and migratory. This striking transition between non-migratory versus migratory behaviors is traditionally studied in the context of cells on a flat surface in 2D. These collective cellular behaviors have been widely explored in monolayers of epithelial cells that form two-dimensional (2D) flat surfaces, from both biophysics and cell biology perspectives. However, they are not well-adapted to make predictions for natural epithelia, which are typically found to form highly curved surfaces, where the radius of curvature can be comparable to a few cell lengths. Epithelial tissues also comprise various topologies – spheres, ellipsoids, tubes, and saddle points — in native structures such as embryos, alveoli, airways, vessels, and branching bifurcations. How surface curvature affects the way a cell collective moves remains largely unknown; furthermore, how cells become jammed and unjammed during the maturation of a cell monolayer growing on a curved surface remains unclear. Further, whereas previous modeling efforts have focused more on the mechanics and migratory behavior of cells within a single monolayer, the mammalian epidermis is a multilayered epithelial tissue. Although the developing epidermis is highly dynamic, the time-dependent mechanics (i.e., rheology) of epidermal development remains elusive. There are two key unresolved questions: (1) what cues drive epidermal development, and (2) how does the mechanics of the epidermis depend on the timescale of measurement? There is an urgent need to develop theoretical and computational models for these critical scenarios. I will develop an integrated computation modeling framework to elucidate the biomechanics of collective cell behavior beyond the conventionally studied two-dimensional settings, including curved surfaces and multilayered 3D epidermis. I will also create a novel model that addresses the biomechanical couplings between nuclear morphologies and epithelial proliferation.