Competing signaling pathways controls electrotaxis

Abstract

Understanding how cells migrate following exogenous cues is one of the most fundamental questions for biology, medicine, and bioengineering. Growing evidence shows that electrotaxis, the directed cell migration toward electric potential gradients, represents a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane components and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell to respond to an electric field is still poorly understood. Here, we develop a mechanistic model that explains and recapitulate electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that simultaneous and asymmetric distribution of charged membrane receptors towards the anode and the cathode establishes multiple cooperative and competing stimuli for downstream signaling pathways. The resulting polarization of signals controls the actomyosin network dynamics, directing the anodal and cathodal migration of the cell. Our theoretical framework rationalizes the physical processes that determine electrotaxis across cell types and provides a physical framework to test multiple electrotactic pathways. These results together show us how to control cell migration to, e.g., enhance, cancel, or switch directed cell migration, which opens up new avenues not only to promote tissue regeneration or arrest tumor progression but also to design better biomimetic-engineered tissue constructs.