Transepithelial potential as a novel biomarker and therapeutic target for epithelial disease and regeneration

Abstract

The transepithelial potential (TEP) is a stable, long-range bioelectrical gradient maintained across epithelial barriers, generated primarily by polarized ion transport mechanisms such as the Na⁺/K⁺-ATPase and epithelial sodium channels (ENaC). Ranging from a few millivolts to over one hundred millivolts, this potential is not a passive electrical property but an active physiological signal integral to epithelial function. This review synthesizes current understanding of TEP formation, dynamic regulation, and multifaceted roles across organ systems. We emphasize its critical involvement in maintaining epithelial homeostasis, directing wound healing, and orchestrating tissue regeneration. Injury triggers localized TEP collapse, generating endogenous electric fields (EFs) of significant strength (40–200 mV/mm) that serve as potent directional cues guiding collective cell migration, proliferation, and differentiation to coordinate repair. Advances in biophysical instrumentation—including minimally invasive microneedle arrays, wearable sensors, and non-invasive field mapping devices—now enable precise, real-time spatial mapping of TEP dynamics in health and disease. Beyond physiology, TEP has emerged as a key diagnostic marker in pathologies such as cystic fibrosis (via nasal potential difference measurements) and retinal disorders like Age-related Macular Degeneration (AMD). Furthermore, TEP modulation represents a promising therapeutic target for bioelectric interventions, including ion channel pharmacology and exogenous electrical stimulation. This comprehensive overview highlights the fundamental biophysical and biological significance of TEP, bridges molecular mechanisms with tissue-level outcomes, and outlines its rapidly emerging potential in clinical diagnostics, regenerative medicine, and bioelectronic therapeutics.