Review
Electrical fields in wound healing—An overriding signal that directs cell migration

https://doi.org/10.1016/j.semcdb.2008.12.009Get rights and content

Abstract

Injury that disrupts an epithelial layer instantaneously generates endogenous electric fields (EFs), which were detected at human skin wounds over 150 years ago. Recent researches combining molecular, genetic and imaging techniques have provided significant insights into cellular and molecular responses to this “unconventional” signal. One unexpected finding is that the EFs play an overriding guidance role in directing cell migration in epithelial wound healing. In experimental models where other directional cues (e.g., contact inhibition release, population pressure etc.) are present, electric fields of physiological strength override them and direct cell migration. The electrotaxis or galvanotaxis is mediated by polarized activation of multiple signaling pathways that include PI3 kinases/Pten, membrane growth factor receptors and integrins. Genetic manipulation of PI3 kinase/Pten (Phosphoinositide 3-kinases/phosphatase and tensin homolog) and integrin β4 demonstrated the importance of those molecules. The electric fields are therefore a fundamental signal that directs cell migration in wound healing. One of the most challenging question is: How do cells sense the very weak electric signals? Clinically, it is highly desirable to develop practical and reliable technologies for wound healing management exploiting the electric signaling.

Introduction

Cell migration into the wound is an essential part of all wound healing in mammals. This response precedes and positions cells at appropriate places for proliferation and differentiation. Impaired re-epithelialization due to defective cell migration into the wound is characteristic of chronic wounds in the elderly, decubitus ulcers, and venous stasis ulcers of the skin [1], [2], [3], [4], [5], [6]. In some cases, the impaired ability of the epithelium to migrate across the wound bed rather than inadequate cell proliferation is responsible for the failure of re-epithelialization [7], [8], [9]. To migrate effectively to heal a wound, our body's cells must know not only when to migrate but, very importantly, in which direction. The cues that might give cells this direction include: (1) injury stimulation per se; (2) gradients of chemoattractants; (3) contact inhibition release; (4) wound void—provision of space; (5) population pressure—growth of adjacent cells pushes cells into the wound; and (6) changes in mechanical force following injury [3], [10], [11], [12] (Fig. 1).

The endogenous electric fields (EFs) at wounds have also been proposed as a directional cue that directs the cells to migrate in wound healing [13], [14], [15], [16]. Studies in the last decade have provided convincing evidence that there is a role for EFs in wound healing [17], [18], [19], [20], [21], [22]. Significantly, this role may be far more important than expected because they override other directional cues in guiding cell migration in wound healing [23]. Some important molecules have been identified in mediating the electric signals, for example EGF receptors, integrins, V-ATPase H+ pump, and PI3 kinase/Pten (Phosphoinositide 3-kinases/phosphatase and tensin homolog) [23], [24], [25], [26], [27], [28], [29]. Many aspects of the effects of EFs have been covered in some recent reviews [21], [22], [27], [30], [31], [32]. This review will focus on the generation of the endogenous wound EFs, the hierarchical role of the electric signals in guiding cell migration and some insights into the molecular and genetic mechanisms.

Section snippets

Endogenous wound electric fields

Naturally occurring electric currents at human skin wounds were measured over 150 years ago (Fig. 2A). German physiologist Emil Du Bois-Reymond (1818–1896), a founder of modern electrophysiology documented in details the electric activities associated with nerve excitation, muscle contraction and wounds [33], [34]. While electric activities in the nervous system and muscles are prevailing concepts in science, the wound EFs have remained very poorly understood and largely ignored. Modern

Transepithelial potential difference

Polarized epithelia transport ions directionally and maintain trans-epithelial potentials (TEP) (Fig. 2C). Corneal epithelium for example, possesses channels and pumps that transport cations (mainly Na+) inwards to the basal side, and anion (Cl) out apically into tear fluid. This is electrogenic—bringing more positive charges to the basal side and more negative charges to the apical side [48], [49], [50], [51]. The outer cells of corneal epithelium are connected by tight junctions and form the

Manipulation of epithelial transportation of ions and the effects on wound electric fields

Polarized distribution of ion channels and pumps in epithelia maintains the vectorial ion transport [54], [61], [66]. Corneal epithelium actively absorbs Na+ from and secretes Cl into the tear film through Na+ channel (ENaC) and Cl channels (e.g., CFTR cystic fibrosis transmembrane conductance regulator) on the apical side and Cl transporters on the basal side [76], [77], [78], [79] (Fig. 3). The relative magnitudes of net Cl secretion and Na+ absorption largely dictate the electrogenic

Electric fields are an overriding guidance cue that directs cell migration in wound healing

Electric signals are shown experimentally to be an overriding guidance cue for directional cell migration in wound healing. Although EFs are applied experimentally, the same EFs occur naturally in vivo (described in Sections 2 Endogenous wound electric fields, 3 Physiological basis of the generation of wound electric fields, 3.1 Transepithelial potential difference, 3.2 Wound electric fields, 3.3 The endogenous electric fields are regulated spatially and temporally, 4 Manipulation of epithelial

How cells sense and transduce the electric signals

Some key signaling mediators for electric field-directed cell migration have been identified recently. These exciting discoveries offer great opportunities to answer one of the key questions—how cells sense the small extracellular electric fields.

Conclusion and perspectives

Naturally occurring EFs are an intrinsic property of wounds. EFs of physiological strength override co-existing guidance cues and direct cell migration in epithelial wound healing. The in vivo EFs are likely to serve as an integrator to organize cells into structured tissues in wound helanig, developmetn and tissue regeneration. But, how? One of the fundamental questions remains to be answered is how cells sense the EFs. Are there specific sensor molecules or the EFs highjack whatever available

Acknowledgments

I thank the Wellcome Trust for continuous support, and support from the Mearns’ Trust, British Heart Foundation, Royal Society (London), Royal Society of Edinburgh for supporting me at various stages of my careers in the UK. The writing up is supported by an UC Davis Dermatology startup-fund. I am grateful to Professor Zhengguo Wang for introducing the fascinating notion that the wounds have electric fields. I thank Professors Colin McCaig and John Forrester for support and for allowing me to

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