Impairment of HIF-2α Expression Induced the Compensatory Overexpression of the HIF-1α/SDF-1 Axis to Promote Wound Healing

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1a and the upregulation of HIF-2a. Notably, HIF-2a impairment resulted in the compensatory overexpression of HIF-1a and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2a kd/null mice (kd/null), the functions of HIF-2a in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2a, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1a, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2a in the inflammation phase of the wound healing process through the HIF-1a/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2a is a new concept for wound therapy.