Osmolarity-independent electrical cues guide rapid response to injury in zebrafish epidermis

Andrew S. Kennard, Julie A. Theriot

Preprint posted on 5 August 2020

Article now published in eLife at

Charging the cellular migration- dissecting electrical cues that guide the wound response!

Selected by Ankita Jha

Categories: cell biology


Epithelial tissue can act as a strong resistance barrier by minimizing the passive flow of ions down the concentration gradients that maintain trans-epithelial potential (TEP). This can generate a significant electrical field around the tissue. Wounding or injury in the epithelial tissue can cause electric flow currents in the direction of the injury, which can be maintained for a long time. This regulates the wound response by guiding cells to migrate and cover the wound (Reid and Zhao, 2014). Cell migration in response to the electrical field has been hypothesized to be controlled by actin alignment, reorganization, and distribution of plasma membrane proteins and organelles (Robinson KR. 1985). But what are the electrical cues in-vivo that guide cell polarization and migration during a wound response? In this preprint, the authors test the role of osmolarity, tonicity and the electrical field in the wound response.


Illustration provided by the authors, showing changes in TEP with tissue wound that generates electric flow and initiates cell migration.

Major findings-

  • Tissue laceration in zebrafish tail leads to tissue contraction and induces a migratory response which is concomitant with calcium spikes at different rates in the first few minutes of the injury.
  • Injury leads to actin polarization with the formation of actin-rich ruffles different from isolated keratocytes.
  • This polarization was evident up to several hundred micrometers away from the laceration.
  • Osmolarity- Cell speed was strongly reduced in sodium chloride solution compared to other isosmotic solutions, which suggested that wound-induced cell migration depends on the local sodium-chloride ionic activity, not just the osmotic effect. Cells largely lacked polarization and actin reorganization in sodium chloride isosmotic solution.
  • Tonicity-Authors show that cell migration and wound response is independent of the tonicity of the isosmotic solutions (identical concentration of different salts inducing water flow).
  • Electrical field- One of the cues during injury is the disruption of trans-epithelial potential, which is maintained by sodium and chloride ions across the skin. Authors show that cellular wound response is directional towards the cathode and the cells respond in a polarized fashion towards exogenous wound cues.

 What I like about the preprint-

The idea that cells respond to differences in the local electrical field around tissues have been put forward some time ago, but a careful dissection of mechanisms has yet not been achieved. This work focusses on carefully dissecting different hypotheses that would be responsible for polarized cell migration after injury in zebrafish. This work also reinforces the idea that trans-epithelial potential and generation of electrical flows is an important factor to be considered in wound response in-vivo.

 Questions to the authors-

  • This work shows that trans-epithelial potential (TEP) is important and disruption of TEP can induce cell polarization. It has been suggested that TEP is maintained by ion channels and sodium-potassium pumps. With wounding, electrical flows are generated locally eliciting cellular responses. Could the authors suggest how are these flows maintained over time?
  • It has also been shown that cell polarization is evident several hundred microns away from the wound. How is this response elicited when the changes in the electrical flows are so local? Or can small lacerations cause large scale electrical flows?


Robinson KR. The responses of cells to electrical fields: a review. J Cell Biol. 1985;101(6):2023-2027. doi:10.1083/jcb.101.6.2023

Reid B, Zhao M. The Electrical Response to Injury: Molecular Mechanisms and Wound Healing. Adv Wound Care (New Rochelle). 2014;3(2):184-201. doi:10.1089/wound.2013.0442


Tags: #cellmigration

Posted on: 28 October 2020


Read preprint (No Ratings Yet)

The author team shared

Author Response

Thank you for your thoughtful summary of our work! Here are our thoughts on your questions:

  • This work shows that trans-epithelial potential (TEP) is important and disruption of TEP can induce cell polarization. It has been suggested that TEP is maintained by ion channels and sodium-potassium pumps. With wounding, electrical flows are generated locally eliciting cellular responses. Could the authors suggest how are these flows maintained over time?

There are two main factors contributing to long-lived electrical currents. First the resistance to ion flow has to be fairly high, so that the flow of ions out of the tissue will not occur all at once. A hydraulic analogy is appropriate: the electrical potential driving ion flow out of the epidermis is analogous to a lake that is being drained by a river. The lake will drain slower through a small river that permits less water flow than through a large river. In our system we believe this could be accomplished if ion flow were restricted to the narrow spaces between cells within the epidermis (Robinson and Messerli, 2003).

The second contributing factor is the gradual replenishment of ions by compensatory inward ion flow distant from the wound. In the hydraulic analogy, rain can fill up the lake and prevent it from running dry. In the epidermis, small ion flows occur throughout the epidermis (see Reid et al., 2007 Fig 5d for a mapping of these currents across an unwounded zebrafish larva). While the magnitude of these flows is small, integrated across the rest of the unwounded skin, they can be substantial. Furthermore, it is possible that wounding could induce changes to ion flows elsewhere in the skin, by opening channels or increasing the activity of the pumps that maintain the TEP in homeostasis. For example, in the corneal epithelium of the eye, which is a well-studied model system for wound-induced electric currents, chloride has been identified as a major contributor to the wound-induced current, and there is evidence that chloride channels become upregulated throughout corneal tissue following wounding (Vieira et al. 2011). Building on our work, it would be very informative to map the current flows around the zebrafish larvae during wound healing to see how they are affected by injury. Combined with pharmacological inhibition of ion channels, this readout could be very useful for pinning down the molecular basis of electrical activity in the zebrafish epidermis, particularly during wound healing.

  • It has also been shown that cell polarization is evident several hundred microns away from the wound. How is this response elicited when the changes in the electrical flows are so local? Or can small lacerations cause large scale electrical flows?

We favor a model in which lacerations induce electrical flows over at least 200-300 microns, the same range of tissue that becomes polarized to a wound following injury. Indeed, the fact that alterations to electrical potentials can rapidly induce changes in electrical activity across long distances is one of the conceptual advantages of electric fields as a physical coordinating cue. Admittedly, we have not directly measured the electric fields at different locations relative to the wound. However, when this has been done in wounded Xenopus tadpoles, electrical gradients can be measured at least a hundred microns away from the wound (Ferreira et al. 2016).

As we followed the science of the remarkably fast and coordinated wound response in the zebrafish skin, this project led us into the exciting yet technically challenging field of bioelectricity. We were impressed with the deep body of work that laid the foundations for the concept of electric fields in wound healing. We believe a major contribution of this paper is to connect the bioelectric measurements that others have made to specific cytoskeletal responses at the cellular level in vivo. We hope that professional electrophysiologists will be inspired by our work to consider zebrafish an ideal model system for integrating electrical and cell biological analyses for a fuller understanding of wound healing.


Ferreira F, Luxarxi G, Reid B, Zhao M.  Early bioelectric activities mediate redox-modulated regeneration. Development 2016; 143(24): 4582-4594. doi:10.1242/dev.142034

Robinson KR and Messerli MA. Left/right, up/down: the role of endogenous electrical fields as directional signals in development, repair and invasion. BioEssays 2003; 25(8): 759-766. doi: 10.1002/bies.10307

Reid B, Nuccitelli R, Zhao M. Non-invasive measurement of bioelectric currents with a vibrating probe. Nat Protoc 2007; 2(3): 661-669. doi:10.1038/nprot.2007.91

Vieira AC, Reid B, Cao L, Mannis MJ, Schwab IR, Zhao M. Ionic components of electric current at rat corneal wounds. PLoS ONE 2011; 6(2): e17411. doi: 10.1371/journal.pone.0017411

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.


List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.


List by Nadja Hümpfer et al.


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria


List by Dey Lab, Samantha Seah


Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA


List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.


List by Dey Lab, Amanda Haage