Electric field down-regulates CD9 to promote keratinocytes migration through AMPK pathway

Abstract

Endogenous electric field (EF)-directed keratinocytes migration is known to play a key role in the wound re-epithelialization process. Although many molecules and signaling pathways are reported important for directional keratinocytes migration under EF, the underlying mechanism remains unclear. Our previous research found that CD9, a trans-membrane protein, is involved in wound re-epithelialization and CD9 downregulation contributes to keratinocytes migration. In this study, we observed the effect of EF on CD9 expression and keratinocytes migration. The keratinocytes migrated directionally toward the cathode and CD9 expression was down-regulated under EF (200mV/mm). In addition, CD9 overexpression reversed EF-induced migratory speed and the electrotactic response of keratinocytes. Also, we found that EF reduced AMP-activated protein kinase (AMPK) activity. Furthermore, AICAR, an AMPK activator, increased CD9 expression under EF, while compound C, an AMPK inhibitor, decreased CD9 expression in keratinocytes. Our results demonstrate that EF regulates CD9 expression and keratinocytes directional migration, in which AMPK pathway plays an important role.

Bioelectronic microfluidic wound healing

“…Also, p38/MAPK inhibition increases CD9 expression, thus supressing migration.46 Building off that knowledge, it was also shown that keratinocytes subjected to direct current EFs (200mVmm −1 ) will have their CD9 expression down-regulated via the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway. 47 These cumulative factors lead us to believe that if keratinocytes are slowed via an inhibited p38/MAPK pathway (increased CD9 expression), then direct current EFs could down-regulate the CD9 and override the migration inhibition via the alternative AMPK pathway.…”

Do epidermal keratinocytes have sensory and information processing systems?

“…74 It was recently shown that an electric field downregulates CD9, promoting keratinocyte migration through the AMPK pathway. 75 We previously demonstrated that a voltage-gated calcium channel is functionally expressed in human epidermal keratinocytes. 76 On the contrary, a healthy skin surface has a negative electrical potential that is generated by keratinocytes, 77 due to the calcium ion concentration gradient in the epidermis.…”

“…Moreover, during the wound‐healing process, electrical stimulation enhanced epidermal keratinocyte proliferation by modulating the p53–SIVA1 interaction 74 . It was recently shown that an electric field downregulates CD9, promoting keratinocyte migration through the AMPK pathway 75 …”

Bioelectronic microfluidic wound healing: a platform for investigating direct current stimulation of injured cell collectives

“…52 Building off that knowledge, it was also shown that keratinocytes subjected to direct current EFs (200 mV mm −1 ) will have their CD9 expression down-regulated via the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway. 55 The sum of these factors led us to believe that if keratinocytes are slowed via an inhibited p38/MAPK pathway (increased CD9 expression), then direct current EFs could down-regulate CD9 and override the migration inhibition via the alternative AMPK pathway.…”