Modeling emergent tissue organization involving high-speed migrating cells in a flow equilibrium

Abstract

There is increasing interest in the analysis of biological tissue, its organization and its dynamics with the help of mathematical models. In the ideal case emergent properties on the tissue scale can be derived from the cellular scale. However, this has been achieved in rare examples only, in particular, when involving high-speed migration of cells. One major difficulty is the lack of a suitable multiscale simulation platform, which embeds reaction-diffusion of soluble substances, fast cell migration and mechanics, and, being of great importance in several tissue types, cell flow homeostasis. In this paper a step into this direction is presented by developing an agent-based mathematical model specifically designed to incorporate these features with special emphasis on high speed cell migration. Cells are represented as elastic spheres migrating on a substrate in lattice-free space. Their movement is regulated and guided by chemoattractants that can be derived from the substrate. The diffusion of chemoattractants is considered to be slower than cell migration and, thus, to be far from equilibrium. Tissue homeostasis is not achieved by the balance of growth and death but by a flow equilibrium of cells migrating in and out of the tissue under consideration. In this sense the number and the distribution of the cells in the tissue is a result of the model and not part of the assumptions. For purpose of demonstration of the model properties and functioning, the model is applied to a prominent example of tissue in a cellular flow equilibrium, the secondary lymphoid tissue. The experimental data on cell speed distributions in these tissues can be reproduced using reasonable mechanical parameters for the simulated cell migration in dense tissue.Comment: 27 pages, 7 figures v2 major conceptual changes: stronger focus on model architecture; new Fig 6, fitting of migration parameters; reduced Fig 7 (formerly Fig 6), shortened presentation of the application; equation (3) provided in more detail; Fig 5 extende