Directing migration of endothelial progenitor cells with applied DC electric fields

Abstract

Naturally-occurring, endogenous electric fields (EFs) have been detected at skin wounds, damaged tissue sites and vasculature. Applied EFs guide migration of many types of cells, including endothelial cells to migrate directionally. Homing of endothelial progenitor cells (EPCs) to an injury site is important for repair of vasculature and also for angiogenesis. However, it has not been reported whether EPCs respond to applied EFs. Aiming to explore the possibility to use electric stimulation to regulate the progenitor cells and angiogenesis, we tested the effects of direct-current (DC) EFs on EPCs. We first used immunofluorescence to confirm the expression of endothelial progenitor markers in three lines of EPCs. We then cultured the progenitor cells in EFs. Using time–lapse video microscopy, we demonstrated that an applied DC EF directs migration of the EPCs towards the cathode. The progenitor cells also align and elongate in an EF. Inhibition of vascular endothelial growth factor (VEGF) receptor signalling completely abolished the EF-induced directional migration of the progenitor cells. We conclude that EFs are an effective signal that guides EPC migration through VEGF receptor signalling in vitro. Applied EFs may be used to control behaviours of EPCs in tissue engineering, in homing of EPCs to wounds and to an injury site in the vasculature.

The Electrical Response to Injury: Molecular Mechanisms and Wound Healing

“…58 Other more specialized skin cells also respond to applied EFs, for example, vascular endothelial cells 59,60 and microvascular cells, 23 which are responsible for new blood vessel formation. Neurons also grow in response to skin wounds, 61 and nerve growth toward cornea wounds is stimulated and directed by the endogenous wound electric signal.…”

Directed migration of human bone marrow mesenchymal stem cells in a physiological direct current electric field

“…We have investigated the role of EFs in directing the migration of MSCs, and provide evidence that physiological EFs robustly direct and speed MSC migration towards the anode. DC EFs are present naturally at wounds in a variety of different tissues and are a powerful directional guidance cue for epithelial cells, fi broblasts, vascular endothelial cells, keratinocytes, endothelial progenitor cells, and neurons McCaig et al, 2009;Robinson and Messerli, 2003;Trollinger et al, 2002;Yao et al, 2009;Zhao et al, 1996;Zhao et al, 2004;Zhao et al, 2006;Zhao et al, 2011). Directed migration of cells in a DC EF is highly cell-type specifi c, since some cell types migrate cathodally and others anodally (Robinson, 1985).…”

“…In many cases, cells such as rat osteoblasts, bovine chondrocytes, bovine aortic vascular endothelial cells, and mouse endothelial progenitor cells migrate towards the cathode (Chao et al, 2000;Ferrier et al, 1986;Li and Kolega, 2002;Ozkucur et al, 2009;Zhao et al, 2011). However, some cells including rabbit osteoclasts, human osteosarcoma cells, rabbit corneal endothelial cells, and human umbilical vein endothelial cells migrate in the opposite direction, towards the anode (Chang et al, 1996;Ferrier et al, 1986;Ozkucur Z Zhao et al Electrotaxis of bone marrow mesenchymal stem cells Zhao et al, 2004).…”

“…MSCs have been identified in many adult tissues including bone marrow (Pittenger et al, 1999), adipose (Zuk et al, 2002), periosteum (De Bari et al, 2001a;De Bari et al, 2006), and synovial membrane (De Bari et al, 2001b;De Bari et al, 2003;De Bari et al, 2004). They are plastic-adherent fi broblast-like cells, express CD105, CD73 and CD90, lack expression of CD45 (Dominici et al, 2006) and have single-cell inherent ability to differentiate into mesenchymal lineages including bone (Pittenger et al, 1999).…”

Electric current‐induced lymphatic activation

“…One could speculate that cell membrane depolarization of LECs induced by electric stimuli could trigger calcium influx, leading to lymphatic activation like proliferation and migration, although more study is needed for deciphering the mechanism. Further research is needed to determine the functional role of lymphatic vascular electrotaxis in vivo and to investigate possible applications, including stem cell maintenance (9).…”