Abstract
The endogenous electric field (EF)-directed migration of keratinocytes (galvanotaxis) into wounds is an essential step in wound re-epithelialization. Hypoxia, which occurs immediately after injury, acts as an early stimulus to initiate the healing process; however, the mechanisms for this effect, remain elusive. We show here that the galvanotactic migration of keratinocytes was enhanced by hypoxia preconditioning as a result of the increased directionality rather than the increased motility of keratinocytes. This enhancement was both oxygen tension- and preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours. Hypoxic preconditioning (2% O2, 6 hours) decreased the threshold voltage of galvanotaxis to < 25 mV/mm, whereas this value was between 25 and 50 mV/mm in the normal culture control. In a scratch-wound monolayer assay in which the applied EF was in the default healing direction, hypoxic preconditioning accelerated healing by 1.38-fold compared with the control conditions. Scavenging of the induced ROS by N-acetylcysteine (NAC) abolished the enhanced galvanotaxis and the accelerated healing by hypoxic preconditioning. Our data demonstrate a novel and unsuspected role of hypoxia in supporting keratinocyte galvanotaxis. Enhancing the galvanotactic response of cells might therefore be a clinically attractive approach to induce improved wound healing.
Highlights
To migrate effectively to heal a wound, keratinocytes must sense when to migrate and the required direction
Using a model of galvanotactic migration of keratinocytes, we here found the following: (1) the electric field (EF)-guided directional migration of keratinocytes was enhanced by hypoxic preconditioning, with this effect resulting from the increased directionality rather than the motility of keratinocytes; (2) the enhanced keratinocyte galvanotaxis was both oxygen tensionand preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours; (3) hypoxic preconditioning decreased the threshold voltage required for keratinocyte galvanotaxis to < 2 5 mV/mm; (4) hypoxic preconditioning accelerated the healing process in a monolayer wound when the applied EF vector pointed in the default healing direction; and (5) Reactive oxygen species (ROS) may be a link between hypoxic preconditioning and the enhanced galvanotaxis of keratinocytes
As a field strength of 50 mV/mm is comparable with the strength of endogenous wound EFs (42–100 mV/mm) as measured experimentally in animals and humans[2], this strength was selected as the EF strength in our study to explore the role of hypoxia in keratinocyte galvanotaxis
Summary
To migrate effectively to heal a wound, keratinocytes must sense when to migrate and the required direction. Using a model of galvanotactic migration of keratinocytes, we here found the following: (1) the EF-guided directional migration of keratinocytes was enhanced by hypoxic preconditioning, with this effect resulting from the increased directionality rather than the motility of keratinocytes; (2) the enhanced keratinocyte galvanotaxis was both oxygen tensionand preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours; (3) hypoxic preconditioning decreased the threshold voltage required for keratinocyte galvanotaxis to < 2 5 mV/mm; (4) hypoxic preconditioning accelerated the healing process in a monolayer wound when the applied EF vector pointed in the default healing direction; and (5) ROS may be a link between hypoxic preconditioning and the enhanced galvanotaxis of keratinocytes
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