Multicellular Agent-Based Computational Modeling Approaches to Investigate Cell- and Tissue Scale Effectors of Collective Migration Within an In Vivo Context

The coordinated migration of cells in a collective is a feature of many important biological processes including wound healing, cancer invasion, tissue regeneration, and morphogenesis during development. During collective migration, multiple distinct behaviors of individual cells emerge and can be analyzed. At the cellular length scale, motile cells within collectively migrating tissues typically arrange into leader and follower rows with distinct adhesive properties and protrusive behaviors. Migratory cells at the leading edge polarize and exhibit persistent directed migration in a process termed cohesotaxis. Follower cells intercalate, or rearrange relative to one another, resulting in spreading of the tissue mass. Additionally, intercellular adhesion along with contractility of the cortical cytoskeleton of individual cells results in a fluid-like surface tension across the tissue resulting in tissue reorganization. These cell- and tissue- scale mechanisms driving collective cell migration and tissue reorganization have been characterized experimentally using ex vivo tissue preparations from biological systems such as the Xenopus laevis embryo. However, these explants are limited in that they lack the context of the in vivo environment from which they were removed. Moreover, many of these cellular and tissue-scale processes are difficult to perturb in isolation or in vivo. This dissertation explores the development of computational methods to investigate these phenomena in silico through multicellular agent-based computational models. I develop and describe Cellular-Potts models to understand the effect of cohesotaxis, intercalation, and tissue geometry on the rate of collective migration of tissue in the developing embryo. I create Cellular-Potts and vertex models to investigate the influence of tissue surface tension in explant tissues. Finally, I describe a novel DLP bioprinted platform for quantifying the micronewton-scale biomechanical forces generated in these explants in representative in vivo geometries. In doing so, I explore relative roles of multiple cell- and tissue- scale effectors of collective migration with respect to the gastrula stage Xenopus laevis embryo. This work represents progress toward the long-term goal of developing a virtual gastrula-stage embryo.