Tissue Fluidity: A Double-Edged Sword for Multicellular Patterning

The organization of cells into spatial patterns is a fundamental aspect of multicellularity. One major mechanism underlying tissue patterning is adhesion-based cell sorting, in which a heterogeneous mixture of different cell types spontaneously separates into distinct domains based on cell type-specific differences in adhesion protein expression. While there is ample evidence that cells can sort by adhesive compatibility, much less is known about how the biomechanical properties of the tissue control the proficiency of cells to sort. Here, we identify tissue fluidity—the extent to which cells can move freely within a tissue—as a critical regulator of adhesion-based sorting. First, we develop a first-principles biophysical model integrating both tissue fluidity and adhesion-based sorting, and demonstrate that this model can quantitatively reproduce experimentally measured sorting dynamics in a fibroblast cell culture assay. We go on to show that altering tissue fluidity by any mechanism in the model (i.e., by varying cell motility, cell–cell adhesion, or tissue viscosity) leads to substantial changes in the rate or accuracy of sorting (or both). We further demonstrate that the balance between cell migration, which acts to fluidize the tissue, and homotypic cell–cell adhesion, which acts to solidify the tissue, sensitively tunes a fundamental trade-off between the rate and accuracy of sorting— such that sorting can only occur when migration and adhesion are tightly coupled. To interrogate the consequences of this coupling requirement experimentally, we varied adhesion protein expression levels in the cell sorting assay, and fit the simulations to the observed sorting dynamics to infer the energies of migration and adhesion across experimental conditions. Intriguingly, our results suggest that cells may naturally scale their motility strength with their adhesion strength – thereby maintaining a permissive fluidity for sorting. Overall, our results indicate that tissue fluidity must be tightly regulated in order for sorting to occur, and that cells may have evolved a mechanism to naturally co-regulate their mechanical properties in order to maintain a patterning-competent fluidity.