Abstract
Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism.
Highlights
Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment
MiR-210 is a unique microRNA that possesses an hypoxia response element (HRE) and it is exclusively regulated in hypoxia by hypoxia inducible factor-1 (HIF-1) signaling[6] and it is modulated in a dose-dependent manner by oxygen7. miR-210 is ubiquitously expressed and influences the expression of a cluster of genes that are involved in processes highly relevant for energy metabolism and for tissue regeneration including angiogenesis, cell proliferation/apoptosis, and metabolic adaptation[8]
These repressed levels of miR-210 reflect the impaired HIF-1 signaling in diabetic wounds[1] since they could be reversed when HIF-1 signaling was restored by local treatment with Dimethyloxalylglycine (DMOG) known to be able to overcome the repressing effect of diabetes on HIF-1 signaling[2] (Fig. 2e, f)
Summary
Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. MiR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Wound healing is a complex process with high energy demands that involves several cellular compartments including keratinocytes, fibroblasts, endothelial and immune cells. The energy balance in diabetic wounds is even more difficult to achieve since hypoxia is more profound than in normoglycemic wounds[1] and the cellular reactions to hypoxia are impaired in diabetes[2] due to repressed hypoxia inducible factor-1 (HIF-1) signaling[3]. Local pharmacological reversal of the repressed HIF-1 signaling in diabetes is followed by the promotion of wound healing secondary to the improvement of several energy-demanding processes i.e. angiogenesis, dermal and epidermal regeneration[1,4]. Local reconstitution of miR-210 improved wound healing in db/db mice by restoring metabolic balance and improving processes central to wound healing
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