Regulation of Cell Function via Extracellular Biophysical Environment: A Theoretical- Experimental Approach

Abstract

Regulatory promise of electric field (EF) as a non-pharmacological, non-invasive tool to control cellular functions is of great therapeutic interest. However, biophysical mechanisms for the cell-EF interactions are not understood. We developed a theoretical-experimental approach to investigate EF effects on cells in electrode-free physiologically-relevant configuration, i.e. with cells attached to a substrate. Cell is modeled as a membrane-enclosed hemisphere with realistic parameters. Our numerical results demonstrated that EF frequency is the major parameter that controls the mechanism of EF interactions with cells in realistic environment. Non-oscillating or low-frequency EF leads to charge accumulation on the cell surface membrane and results in field screening from the cytoplasm, suggesting that in this regime, cell responses are regulated by EF interactions with the surface membrane receptors. In contrast, high-frequency EF penetrates the cell membrane and reaches cell cytoplasm, where it may directly activate intracellular responses. Theoretical simulation predicts the non-uniform distribution of the induced field within the cell membrane, which depends on the applied EF frequency. Importantly, substrate properties significantly affect both magnitude and distribution of the induced field on the cell membrane, underscoring the need for a comprehensive, physiologically-relevant modeling approach for EF-cell interactions. These theoretical predictions were confirmed in our experimental studies of the effects of applied EF on responses of vascular cells. Results show that non-oscillating EF increases vascular endothelial growth factor (VEGF) expression while field polarity controls cell adhesion rate. High-frequency, but not low-frequency, EF provides differential regulation of cytoplasmic focal adhesion kinase and VEGF expression depending on the substrate, with increased expression in cells cultured on RGD-rich synthetic hydrogels, and decreased expression for basement membrane (matrigel) culture. These results advance our understanding of complex mechanisms underlying cell-EF interactions and may contribute to future EF-based therapies.