Electrically stimulated cell migration and its contribution to wound healing

Abstract

Naturally occurring electric fields are known to be morphogenetic cues and associated with growth and healing throughout mammalian and amphibian animals and the plant kingdom. Electricity in animals was discovered in the eighteenth century. Electric fields activate multiple cellular signaling pathways such as PI3K/PTEN, the membrane channel of KCNJ15/Kir4.2 and intracellular polyamines. These pathways are involved in the sensing of physiological electric fields, directional cell migration (galvanotaxis, also known as electrotaxis), and possibly other cellular responses. Importantly, electric fields provide a dominant and over-riding signal that directs cell migration. Electrical stimulation could be a promising therapeutic method in promoting wound healing and activating regeneration of chronic and non-healing wounds. This review provides an update of the physiological role of electric fields, its cellular and molecular mechanisms, its potential therapeutic value, and questions that still await answers.

The Dynamics of the Skin’s Immune System

“…The skin maintains a net negative charge relative to the tissue laying underneath it. In the case of an injury, ion leakage occurs, creating a voltage gradient throughout the wound site [406]. The application of a voltage gradient in the wound activates signaling molecules that are critical for wound healing such as integrins, epidermal growth factor receptors, and phosphoinositide 3 kinases [407,408].…”

Electrical stimulation in bone tissue engineering treatments

“…Previous in vitro experiments that exposed cells and/or scaffolds to EStim, demonstrated its ability to influence cell functions associated with enhanced bone healing [7][8][9][10][11][12][13][14]. These experiments were conducted on a variety of different cell types; bone marrow-derived mesenchymal stem cells (BM-MSC), from human and animal origin [10,11,[15][16][17][18][19][20][21][22][23][24][25]; adipose-derived mesenchymal stem cells (AT-MSC) [11,20,[26][27][28][29][30], mouse osteoblast-like cells [31][32][33] and more recently, human dental pulp stem cells (DPSC) [34].…”

“…For decades, electrical stimulation (EStim) has been studied and used successfully in clinical practice to stimulate bone healing (reviewed in [6]). While the detailed mechanisms by which EStim promotes healing are poorly understood, several recently published in vitro studies suggest that EStim's pro-healing effect is due to its influence on the behavior and/or function of bone-forming stem cells, such as migration [7,8], proliferation [9], differentiation [10,11], mineralization [12], extracellular matrix deposition [13], and attachment to scaffold materials [14]. Importantly, all these cell behaviors/functions that are central to healing could potentially be used to optimize outcomes in BTE treatments.…”

Membrane potential (Vmem) measurements during mesenchymal stem cell (MSC) proliferation and osteogenic differentiation

“…Only recently have we begun to understand the mechanisms, at a cellular level, by which EStim affects bone healing in this way. In several recent experiments others and we exposed cells, in culture, to externally applied EStim and observed major changes in cell behaviors like, proliferation (Guo et al, 2012; Sebastian et al, 2015; Qi et al, 2018), differentiation (Hernández et al, 2016; Mobini et al, 2017a; Eischen-Loges et al, 2018), migration (Jahanshahi et al, 2013; Yuan et al, 2014; Tai, Tai & Zhao, 2018) and over-all cell cycle progression (Griffin et al, 2013). While changes in endogenous bioelectric activity have been shown to play a crucial role in embryologic development and regeneration, and externally applied EStim has been shown to affect important cell functions involved in regeneration, the role V mem plays in regulating these functions is still poorly understood.…”