Electrically-stimulated cellular and tissue events are coordinated through ion channel-mediated calcium influx and chromatin modifications across the cytosol-nucleus space

Electrical stimulation (ES) through biomaterials and devices has been implicated in activating diverse cell behaviors while facilitating tissue healing process. Despite its significance in modulating biological events, the mechanisms governing ES-activated cellular phenomena remain largely elusive. Here, we demonstrated that millisecond-pulsed temporal ES profoundly impacted a spectrum of cellular events across the membrane-cytosol-nuclear space. These include activated ion channels, intracellular calcium influx, actomyosin contractility, cell migration and proliferation, and secretome release. Such events were coordinated mainly through ES-activated ion channels and calcium oscillation dynamics. Notably, ES increased the chromatin accessibility of genes, particularly those associated with the ES-activated cellular events, underscoring the significance of epigenetic changes in ES-induced behavioral outcomes. We identified histone acetylation (mediated by histone acetyltransferases), among other chromatin modifications, is key in reshaping the chromatin landscape upon ES. These observations were further validated through experiments involving ex vivo skin tissue samples, including activated ion channels and calcium influx, increased cell proliferation and actomyosin contractility, elevated secretome profile, and more accessible chromatin structure following ES. This work provides novel insights into the mechanisms underlying ES-activated cell and tissue events, ultimately guiding design principles for the development of electrical devices and materials effective for tissue repair and wound healing.