UCMSCs-Derived Exosomal circHIPK3 Restrains Oxidative Stress and Inflammation by Downregulating the Stability of HMGB1 mRNA via Recruiting UPF1 in Diabetes Foot Ulcer

Abstract

Excessive oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs) are significant barriers to wound healing in diabetic foot ulcers (DFUs). Umbilical cord mesenchymal stem cells (UCMSCs)-derived exosomal circular RNA homeodomain-interacting protein kinase three (circHIPK3) exerts protective effects on HUVECs under high-glucose (HG) conditions. Our objective was to elucidate the downstream mechanisms through which UCMSCs-derived exosomal circHIPK3 modulates oxidative stress and inflammation in cellular and mice models of DFU. The type II diabetic db/db mice model, HG-induced HUVECs, and HG-treated human dermal microvascular endothelial cells (HDMECs) were used to investigate the mechanism of UCMSCs-derived exosomal circHIPK3. HG induced oxidative stress and inflammation in HUVECs, which were attenuated by UCMSCs-derived exosomal circHIPK3. Next, UCMSCs-derived exosomal circHIPK3 reduced HG-induced HUVECs' oxidative stress and inflammation by downregulating high mobility group box 1 (HMGB1). Furthermore, up-frameshift protein 1 (UPF1) reduced the stability of HMGB1 mRNA through direct interaction. Additionally, UCMSCs-derived exosomal circHIPK3 alleviated HG-induced oxidative stress and inflammation in HUVECs by upregulating UPF1 expression. UPF1 protected HUVECs from HG-induced oxidative stress and inflammation by decreasing HMGB1 mRNA stability. UCMSCs-derived exosomal circHIPK3 also enhanced wound healing in a DFU mice model and reduced oxidative stress and inflammation in HG-treated HDMECs. Overall, UCMSCs-derived exosomal circHIPK3 suppressed HG-stimulated oxidative stress and inflammation, thereby promoting wound healing in both cellular and animal DFU models through the UPF1/HMGB1 axis. These findings suggested that the UCMSCs-derived exosomal circHIPK3/UPF1/HMGB1 axis represents a promising therapeutic target for treating DFU.

Keywords: HMGB1; HUVECs; UCMSCs‐derived exosomal circHIPK3; UPF1; inflammation; oxidative stress.