VH298-loaded extracellular vesicles released from gelatin methacryloyl hydrogel facilitate diabetic wound healing by HIF-1α-mediated enhancement of angiogenesis

by Selleckchem | Aug 03 2023

Endothelial malfunction is responsible for impaired angiogenesis in diabetic patients, thereby causing the delayed healing progress of diabetic wounds. Exosomes or extracellular vesicles (EVs) have emerged as potential therapeutic vectors carrying drug cargoes to diseased cells. In the present study, EVs were reported as a new treatment for diabetic wounds by delivering VH298 into endothelial cells. Firstly, EVs derived from epidermal stem cells (ESCs) were loaded with VH298 (VH-EVs), and the characteristics of VH-EVs were identified. VH-EVs showed promotive action on the function of human umbilical vein endothelial cells (HUVECs) in vitro by activating HIF-1α signaling pathway. VH-EVs were also found to have a therapeutic effect on wound healing and angiogenesis in vivo. We further fabricated gelatin methacryloyl (GelMA) hydrogel for sustained release of VH-EVs, which possessed high biocompatibility and proper mechanical properties. In diabetic mice, GelMA hydrogel containing VH-EVs (Gel-VH-EVs) effectively promoted wound healing by locally enhancing blood supply and angiogenesis. The underlying mechanism for enhanced angiogenesis was possibly associated with the activation of HIF-1α/VEGFA signaling pathway. Collectively, our findings suggest a promising EV-based strategy for the VH298 delivery to endothelial cells and provide a new bioactive dressing for diabetic wound treatment. STATEMENT OF SIGNIFICANCE: The angiogenic dysfunction is the main cause of diabetic wound unhealing. Extracellular vesicles (EVs) have been reported to be helpful but their efficacy is limited for angiogenesis in cutaneous regeneration. VH298 holds great promise to improve angiogenesis by stabilizing HIF-1α which is reported at low level in diabetic wounds. Here, we loaded EVs with VH298 (VH-EVs) to exert an on-target enhancement of proangiogenic capacity in diabetic wound. Then, we applied a photo-crosslinkable hydrogel, gelatin methacryloyl (GelMA) containing VH-EVs (Gel-VH-EVs) as a convenient biomaterial and an adaptable scaffold for sustained releasing VH-EVs. The results showed significant therapeutic effect of Gel-VH-EVs on skin defect repair. Our findings suggest a promising EVs-based drug delivery strategy and a new functional wound dressing for patients.

Comments:

The study you mentioned focuses on the potential use of extracellular vesicles (EVs) as a therapeutic approach for diabetic wounds. The impaired angiogenesis observed in diabetic patients is attributed to endothelial malfunction. EVs, specifically those derived from epidermal stem cells (ESCs) and loaded with VH298 (VH-EVs), were investigated as a means to deliver VH298 to endothelial cells and promote wound healing.

The study first characterized the VH-EVs, confirming their properties. In vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that VH-EVs enhanced the function of these cells by activating the HIF-1α signaling pathway. In addition, VH-EVs were found to have therapeutic effects on wound healing and angiogenesis in vivo.

To enable sustained release of VH-EVs, the researchers developed a gelatin methacryloyl (GelMA) hydrogel. This hydrogel exhibited high biocompatibility and appropriate mechanical properties. When GelMA hydrogel loaded with VH-EVs (Gel-VH-EVs) was applied to diabetic mice, it effectively promoted wound healing by enhancing local blood supply and angiogenesis. The enhanced angiogenesis was likely mediated by the activation of the HIF-1α/VEGFA signaling pathway.

Overall, the study highlights the potential of EVs as a strategy for delivering VH298 to endothelial cells and presents Gel-VH-EVs as a bioactive dressing for diabetic wound treatment. The findings suggest that this EV-based therapeutic approach, along with the GelMA hydrogel, holds promise for improving angiogenesis and facilitating the healing process in diabetic wounds.