Friction-based mechanisms of phenotypic segregation in bacterial biofilms

Biofilms are surface-adhered bacterial communities, encased within extracellular matrices of biopolymers, that play many significant roles in health and society. Recent experimental breakthroughs have enabled the detailed characterization of the fundamental mechanical interactions that shape biofilm development, but how phenotypic heterogeneity influences biofilm development remains largely unknown. Here, we discuss our use of mathematical models to identify the mechanisms through which spatiotemporal heterogeneity in the signaling of a key intracellular second-messenger that governs biofilm formation, cyclic diguanylate (c-di-GMP), can affect the organization of Vibrio cholerae biofilms. Recent work from our group has revealed that, contrary to the classical assumption that biofilm formation is a coordinated process, cells within V. cholerae biofilms exhibit substantial heterogeneity in c-di-GMP levels, and that this gives rise to phenotypic segregation: high-c-di-GMP cells are enriched in the core, whereas low-c-di-GMP cells occupy the periphery. Using mathematical modeling, we have found that various forms of differential friction between high- and low-c-di-GMP cells can give rise to this phenotypic segregation. Our findings illustrate how molecular signaling and mechanical interactions can jointly shape biofilm morphogenesis, in a manner echoing the development of more complex multicellular collectives such as eukaryotic tissues.