bioRxiv2025
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 cell types spontaneously separates into distinct domains based on differences in adhesion protein expression. 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 describe a physically well-understood minimal tissue model that can integrate 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 leads to substantial changes in the rate or accuracy of sorting (or both). We further demonstrate that the balance between cell motility, 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 motility and adhesion are tightly coupled. Intriguingly, best fits of the simulations to the experiments across a range of adhesion protein expression conditions 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 for sorting to occur, and that cells may have evolved a mechanism to naturally co-regulate their mechanical properties in order to sustain a patterning-competent fluidity. Statement of SignificanceTissue fluidity, or the ability of cells to freely rearrange within a tissue, is a universal property of multicellular organisms that plays central roles in development, cancer, and wound healing. Here, we identify tissue fluidity as a critical regulator of a major mechanism of multicellular patterning - adhesion-based cell sorting. The results of our combined experimental-computational investigation suggest that tissues can readily tune their fluidity in order to freeze, catalyze, or erase multicellular patterns - carrying significant implications for our understanding of how patterns are formed in development, lost in diseases affecting tissue organization (e.g., cancer), regained through the processes of wound healing and regeneration, and can be engineered in the creation of synthetic organoid and embryoid systems. One sentence summaryBiophysical modeling demonstrates how tissue fluidity is a key regulator of the rate and accuracy of adhesion-based sorting.