Abstract

Injury that disrupts an epithelial layer instantaneously generates hypoxia microenvironment and endogenous electric fields （EFs），which were detected at human skin wounds many years ago respectively.Following injury，vessel function is compromised leading to acute tissue hypoxia and the hypoxic state is sustained further due to rapid influx of inflammatory and mesenchymal cells with a high metabolic demand for oxygen.Local relative hypoxia has been observed in wounds by direct measurement of local oxygen pressure and its necessity in maintaining good angiogenesis during wound healing has been well defined.Changes in systemic and cellular oxygen concentrations induce tightly regulated response pathways that attempt to modulate cell function in hypoxic conditions.Most of these responses occur through the activation of Notch 1 and integrin β1，the inhibition of AMPK pathway and the regulation of tetraspanin CD9 and BNIP3 and its downstream signaling during wound healing.Besides，endogenous electric fields （EFs）are also generated instantaneously after an injury due to the collapse of the trans-epithelial potentials，with the wound center being more negative than the surrounding tissue and thus acting as the cathode of the endogenous EF until wound re-epithelialization is complete and endogenous EFs have been proposed as a directional cue guiding the migration of keratinocytes in wound healing.EFs play an overriding guidance role in directing cell migration in epithelial wound healing and the electrotaxis or galvanotaxis is mediated by polarized activation of multiple signaling pathways that include PI3 kinases/Pten，membrane growth factor receptors and integrins.Moreover，the galvanotactic migration of keratinocytes was enhanced by hypoxia preconditioning as a result of the increased directionality rather than the increased motility of keratinocytes，Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation，Additionally，autophagy as important functional regulator in the electric-enhanced directed motility.