Direct-current (DC) electric fields are present in all developing and regenerating animal tissues, yet their existence and potential impact on tissue repair and development are largely ignored. This is primarily due to ignorance of the phenomenon by most researchers, some technically poor early studies of the effects of applied fields on cells, and widespread misunderstanding of the fundamental concepts that underlie bioelectricity. This review aims to resolve these issues by describing: 1) the historical context of bioelectricity, 2) the fundamental principles of physics and physiology responsible for DC electric fields within cells and tissues, 3) the cellular mechanisms for the effects of small electric fields on cell behavior, and 4) the clinical potential for electric field treatment of damaged tissues such as epithelia and the nervous system.

Cells undergo a variety of physiological processes, including division, migration and differentiation, under the influence of endogenous electrical cues, which are generated physiologically and pathologically in the extracellular and sometimes intracellular spaces. These signals are transduced to regulate cell behaviours profoundly, both in vitro and in vivo. Bioelectricity influences cellular processes as fundamental as control of the cell cycle, cell proliferation, cancer-cell migration, electrical signalling in the adult brain, embryonic neuronal cell migration, axon outgrowth, spinal-cord repair, epithelial wound repair, tissue regeneration and establishment of left-right body asymmetry. In addition to direct effects on cells, electrical gradients interact with coexisting extracellular chemical gradients. Indeed, cells can integrate and respond to electrical and chemical cues in combination. This Commentary details how electrical signals control multiple cell behaviours and argues that study of the interplay between combined electrical and chemical gradients is underdeveloped yet necessary.

Controlling cell division is fundamental. One environmental cue that exerts profound control over both the orientation and frequency of cell division in vivo is a naturally occurring, wound-induced electric field (EF). Wounds in rat corneas generate endogenous EFs in the plane of the epithelial sheet because the transcorneal potential difference (TCPD; +40 mV internally positive) collapses at the wound edge, but is maintained at normal levels at 0.5 mm back from the wound. We manipulated the endogenous EF this creates by using drugs with differing actions. The wound-induced EF controlled the orientation of cell division; most epithelial cells divided with a cleavage plane parallel to the wound edge and perpendicular to the EF vector. Increasing or decreasing the EF pharmacologically, respectively increased or decreased the extent of oriented cell division. In addition, cells closest to the wound edge, where the EF was highest, were oriented most strongly by the EF. Remarkably, an endogenous EF also enhanced the frequency of cell division. This also was regulated by enhancing or suppressing the EF pharmacologically. Because the endogenous EF also regulated the wound healing rate, it may act as one control of the interplay between cell migration and cell division during healing.

Endogenous electric currents generated instantly at skin wounds direct migration of epithelial cells and are likely to be important in wound healing. Migration of fibroblasts is critical in wound healing. It remains unclear how wound electric fields guide migration of dermal fibroblasts. We report here that mouse skin wounds generated endogenous electric currents for many hours. Human dermal fibroblasts of both primary and cell-line cultures migrated directionally but slowly toward the anode in an electric field of 50–100 <!----> mV <!----> mm⁻¹. This is different from keratinocytes, which migrate quickly to the cathode. It took more than 1 <!----> hour for dermal fibroblasts to manifest detectable directional migration. Larger field strength (400 <!----> mV <!----> mm⁻¹) was required to induce directional migration within 1 <!----> hour after onset of the field. Phosphatidylinositol-3-OH kinase (PI3 kinase) mediates cathode-directed migration of keratinocytes. We tested the role of PI3 kinase in anode-directed migration of fibroblasts. An applied electric field activated PI3 kinase/Akt in dermal fibroblasts. Dermal fibroblasts from p110γ (a PI3 kinase catalytic subunit) null mice showed significantly decreased directional migration. These results suggest that physiological electric fields may regulate motility of dermal fibroblasts and keratinocytes differently, albeit using similar PI3 kinase-dependent mechanisms.