Swarming Migration of Co-attracting Mesenchymal Cells into Fractal-Like Epithelial Clusters

Abstract

Cell-secreted factors can function as biochemical “signal relays” to coordinate collective migration over long distances. For instance, cells “co-attract” by releasing chemokines that they also chemotax towards, driving aggregation and cohesion during neural crest development, mesenchymal condensation, and neutrophil homing. Here, we show that mammary epithelial cells cultured in reduced serum conditions display a mutual attraction that results in self-organizing migration patterns. Ordinarily, the migration of spatially dispersed cells in EGF-supplemented media can be understood as a persistent random walk. Instead, cells cultured in EGF-depleted media display directed migration towards each other through co-attraction, resulting in multicellular aggregation. Subsequently, aggregated cells establish cell-cell junctions with E-cadherin, reminiscent of a mesenchymal-to-epithelial transition (MET). Furthermore, cells exhibit substantial morphological changes, extending outward protrusions towards other cells in the proximity. As a consequence, these aggregates display a highly branched, fractal-like architecture. This biological behavior has physical analogies with diffusion-limited aggregation of colloidal particles, which results in a gelation or jamming transition even at very subconfluent cell densities. We implement a computational model based on dissipative particle dynamics that recapitulates clustering and aggregation. These results may reveal new quantitative insights into swarming cell migration during neural crest development, mesenchymal condensation, and tumor metastasis.