Moving Forward Moving Backward: Directional Sorting of Chemotactic Cells due to Size and Adhesion Differences

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Abstract
Differential movement of individual cells within tissues is an important yet poorly understood process in biological development. Here we present a computational study of cell sorting caused by a combination of cell adhesion and chemotaxis, where we assume that all cells respond equally to the chemotactic signal. To capture in our model mesoscopic properties of biological cells, such as their size and deformability, we use the Cellular Potts Model, a multiscale, cell-based Monte Carlo model. We demonstrate a rich array of cell-sorting phenomena, which depend on a combination of mescoscopic cell properties and tissue level constraints. Under the conditions studied, cell sorting is a fast process, which scales linearly with tissue size. We demonstrate the occurrence of “absolute negative mobility”, which means that cells may move in the direction opposite to the applied force (here chemotaxis). Moreover, during the sorting, cells may even reverse the direction of motion. Another interesting phenomenon is “minority sorting”, where the direction of movement does not depend on cell type, but on the frequency of the cell type in the tissue. A special case is the cAMP-wave-driven chemotaxis of Dictyostelium cells, which generates pressure waves that guide the sorting. The mechanisms we describe can easily be overlooked in studies of differential cell movement, hence certain experimental observations may be misinterpreted. The movements of biological cells during the development of an organism depend on the physical characteristics of these cells. Genetic regulation of (developmental) cell movements, in order to have an effect, must operate through or in accordance with these physical properties. With this framework in mind, the authors use a computational model to investigate the interaction of two important phenomena, namely differential adhesion and chemotaxis. Authors Käfer, Hogeweg, and Marée show that this interaction leads to fast cell sorting, a process during which the cells actually move in a specific direction, which can even be opposite to the direction of chemotaxis. The direction of motion does not only depend on intrinsic cell properties (such as cell size or the strength of the homotypic and heterotypic bonds) but also on the pattern formation that takes place during the sorting, as well as on general tissue properties. For example, both the formation of cell clusters and the level of confinement of the tissue can completely turn around the direction of sorting. The authors demonstrate that to fully understand cell tissue dynamics, it is essential to take into account mesoscopic cell properties, such as size, shape, and deformability. Because physically driven processes can profoundly influence the movement of biological cells, this should not be neglected in explanations for observed cell movement patterns.