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-1α 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-1α stability. Because hyperglycemia complicatedly affects HIF-1α 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-1α stability is insufficient.

中文翻译：

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LRG1通过调节HIF-1α稳定性促进角质形成细胞迁移和伤口修复。

上皮再形成是皮肤伤口愈合过程中的一个复杂过程，而细胞迁移是该现象不可或缺的一部分。在这里，我们确定了LRG1作为表皮角质形成细胞迁移的关键调节剂的作用，其中LRG1通过增强HIF-1α稳定性起作用。我们显示，LRG1在鼠皮肤伤口边缘上调，重组人LRG1的添加可加速角质形成细胞迁移和皮肤伤口愈合。此外，我们确定了转录因子ELK3作为LRG1的下游效应子。我们证实，由LRG1操纵的ELK3水平升高可以通过上调HIF-1α稳定性来促进细胞迁移。由于高血糖复杂地影响HIF-1α的稳定性和激活，我们的发现为伤口相关细胞迁移的分子控制提供了见识，并确定了治疗慢性糖尿病伤口的潜在治疗靶标。总之，我们证明LRG1通过角质形成细胞迁移促进伤口修复，对于正常的HIF-1α稳定性不足的糖尿病伤口愈合异常过程至关重要。