Bioelectric Signaling and Voltage-Gated Ion Channels in Appendage Regeneration: A Systematic Literature Review on Bioelectric Blueprints for Tissue Patterning

Abstract

The regenerating appendage must control cell proliferation, migration, differentiation, positional identity, tissue scaling and growth termination in an orchestrated fashion. Emerging evidence suggests that bioelectric signaling contributes as an important physiological layer of information for these processes, in addition to genetic and biochemical signaling. This systematic literature review explores the role of endogenous bioelectric signals and voltage-gated ion channels in appendage regeneration, focusing on their role in tissue patterning and the proposed bioelectric blueprint. Planarians, Xenopus, axolotls, newts, zebrafish and other models of regeneration were used to examine the responses of the electrical properties, changes in membrane potential, ion-channel activity, calcium signaling, gap-junction communication, stem-cell behavior, positional information, and scaling of regeneration. The evidence reviewed here shows that voltage-gated calcium, potassium and sodium channels are involved in transducing electrical signals into intracellular signals that regulate proliferation, migration, differentiation and tissue organization. Other molecular pathways are also linked to bioelectric mechanisms, such as Wnt, FGF, BMP, Notch, Hedgehog, etc. Overall, the results are consistent with a dynamic blueprint based upon electrical fields and states contributing to anatomical polarity, identity, growth and regeneration, both spatially and with time. The findings suggest future applications in tissue engineering, regenerative medicine and in human appendage regeneration.