LRG1 Promotes Keratinocyte Migration and Wound Repair through Regulation of HIF-1α Stability

Re-epithelialization is a complex process during skin wound healing, and cell migration is an integral part of this phenomenon. Here we identified a role for LRG1 as a key regulator of epidermal keratinocyte migration where LRG1 acts via enhancement of HIF-1 alpha stability. We showed that LRG1 is upregulated at murine skin wound edges and that addition of recombinant human LRG1 accelerates keratinocyte migration and skin wound healing. Furthermore, we identified transcription factor ELK3 as a downstream effector of LRG1. We confirmed that elevated ELK3 levels manipulated by LRG1 can promote cell migration through upregulation of HIF-1 alpha stability. Because hyperglycemia complicatedly affects HIF-1 alpha stability and activation, our findings provide insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of chronic diabetic wounds. In conclusion, we demonstrated that LRG1 promotes wound repair through keratinocyte migration and is important for normalization of an abnormal process of diabetic wound healing where HIF-1 alpha stability is insufficient.