Early bioelectric activities mediate redox-modulated regeneration

Abstract

Reactive oxygen species (ROS) and electric currents modulate regeneration; however, the interplay between biochemical and biophysical signals during regeneration remains poorly understood. We investigate the interactions between redox and bioelectric activities during tail regeneration in Xenopus laevis tadpoles. We show that inhibition of NADPH oxidase-mediated production of ROS, or scavenging or blocking their diffusion into cells, impairs regeneration and consistently regulates the dynamics of membrane potential, transepithelial potential (TEP) and electric current densities (J I ) during regeneration. Depletion of ROS mimics the altered TEP and J I observed in the non-regenerative refractory period. Short-term application of hydrogen peroxide (H 2 O 2 ) rescues (from depleted ROS) and induces (from the refractory period) regeneration, TEP increase and J I reversal. H 2 O 2 is therefore necessary for and sufficient to induce regeneration and to regulate TEP and J I . Epistasis assays show that voltage-gated Na + channels act downstream of H 2 O 2 to modulate regeneration. Altogether, these results suggest a novel mechanism for regeneration via redoxbioelectric orchestration.

Regeneration Genetics

“…Although bioelectricity has long been implicated in regeneration (66), the molecular mechanism by which endogenous bioelectrical signals are triggered upon injuries remain elusive. A recent study by Ferreira et al suggests that ROS may act upstream to modulate early bioelectrical activities in amputated tails of Xenopus tadpoles (30). Upon pharmacological inhibition of the ROS source (i.e.…”

“…NADPH oxidase), multiple bioelectrical features like trans-epithelial membrane potential and electrical current densities are disrupted, coinciding with defects in regeneration. Intriguingly, short-term supplement of hydrogen peroxide can consistently modulate bioelectrical activities of the tissue through activation of sodium channels, and it can trigger tail regeneration to occur during the refractory period (30). The downstream targets that bioelectrical signals might regulate remain to be identified (30; 127).…”

“…Intriguingly, short-term supplement of hydrogen peroxide can consistently modulate bioelectrical activities of the tissue through activation of sodium channels, and it can trigger tail regeneration to occur during the refractory period (30). The downstream targets that bioelectrical signals might regulate remain to be identified (30; 127). Thus, early injury signals like hydrogen peroxide may have multiple roles during regeneration, e.g.…”

Ask1 and Akt act synergistically to promote ROS-dependent regeneration in Drosophila

“…ROS acting in signaling after wounding has been subject of extensive research in various organisms and tissues [4,5,[52][53][54][55][56]6,[45][46][47][48][49][50][51]. Here, we have uncovered two scenarios of Ask1 activity: high activity in apoptotic cells, with high levels of P-Thr; and low activity in undamaged cells, where P-Ser83 prevails over P-Thr.…”

Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages

“…Bioelectric signals have been implicated in development (19)(20)(21)(22), wound healing (23)(24)(25) and regeneration (26,27). For example, a wound collapses the transepithelial potential (TEP) difference of an intact epithelial barrier, generating laterally oriented endogenous electric fields (EF) of up to 1.4 V cm −1 , as well as local electric current densities (J I ) of several µA cm −2 .…”