HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration

Epidermal wound repair is a complex process involving the fine orchestrated regulation of crucial cell functions, such as proliferation, adhesion and migration. Using an in vitro model that recapitulates central aspects of epidermal wound healing, we demonstrate that the transcription factor HIF1 is strongly stimulated in keratinocyte cultures submitted to mechanical injury. Signals generated by scratch wounding stabilise the HIF1α protein, which requires activation of the P13K pathway independently of oxygen availability. We further show that upregulation of HIF1α plays an essential role in keratinocyte migration during the in vitro healing process, because HIF1α inhibition dramatically delays the wound closure. In this context, we demonstrate that HIF1α controls the expression of laminin-332, one of the major epithelial cell adhesion ligands involved in cell migration and invasion. Indeed, silencing of HIFa abrogates injury-induced laminin-332 expression, and we provide evidence that HIF1α directly regulates the promoter activity of the laminin α3 chain. Our results suggest that HIF1 contributes to keratinocyte migration and thus to the reepithelialisation process by regulating laminin-332.