IFN-? enhances the therapeutic efficacy of MSCs-derived exosome via miR-126-3p in diabetic wound healing by targeting SPRED1

Background and Aims: The traditional treatment of diabetic wounds is unsatisfactory. Exosomes isolated from bone marrow mesenchymal stem cells (BMSCs) promote the healing of diabetic wounds. However, whether the exosomes secreted by interferon (IFN)-?-pretreated BMSCs have an enhanced therapeutic effect on diabetic wound healing and the relevant mechanisms remain unclear.Methods: In this study, we isolated exosomes from the corresponding superna-tants of BMSCs with (IExos) or without IFN-? treatment (NExos). Human umbili-cal vein endothelial cells (HUVECs) were used to investigate the proliferation, migration, and tube formation under different treatments in vitro. Diabetic mice were induced by intraperitoneal administration of streptozotocin, and a circular full-thickness dermal defect was then made on the back of each mouse, followed by a multisite subcutaneous injection of phosphate buffered saline or exosomes. Hematoxylin-eosin (H & E) staining, Massons trichrome staining, and histological analysis were performed to assess the speed and quality of wound healing.Results: NExos treatment accelerated the healing of diabetic wounds by promoting angiogenesis in vivo and in vitro, and IExos exhibited superior ther-apeutic efficiency. MicroRNA (miR)-126-3p was significantly increased in IExos, and exosomal miR-126-3p promoted angiogenesis and diabetic wound healing via its transfer to HUVECs. miR-126-3p regulates SPRED1 by directly targeting the 30-UTR. Mechanistically, IFN-?-pretreated BMSCs secreted miR-126-3p-enriched exosomes, which enhanced the function of HUVECs and pro-moted angiogenesis via the SPRED1/Ras/Erk pathway.Conclusion: Exosomal miR-126-3p secreted from IFN-?-pretreated BMSCs exhibited higher therapeutic efficacy than NExos in diabetic wound healing by promoting angiogenesis via the SPRED1/Ras/Erk axis.

Automated summary

This study demonstrates that exosomes secreted by IFN-γ-pretreated BMSCs (IExos) have enhanced therapeutic efficacy in diabetic wound healing compared to exosomes without IFN-γ treatment (NExos), by promoting angiogenesis. Specifically, exosomal miR-126-3p secreted from IFN-γ-pretreated BMSCs promotes angiogenesis and diabetic wound healing via the SPRED1/Ras/Erk pathway.