The exosomes are derived from mesenchymal stem cells (MSCs) and may be potentially used as an alternative for cell therapy, for treating diabetic wounds, and aid in angiogenesis. This study, aimed to investigate whether exosomes originated from bone marrow-derived MSCs (BMSCs) preconditioned by deferoxamine (DFO-Exos) exhibited superior proangiogenic property in wound repair and to explore the underlying mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were used for assays involving cell proliferation, scratch wound healing, and tube formation. To test the effects in vivo, streptozotocin-induced diabetic rats were established. Two weeks after the procedure, histological analysis was used to measure wound-healing effects, and the neovascularization was evaluated as well. Our findings demonstrated that DFO-Exos activate the PI3K/AKT signaling pathway via miR-126 mediated PTEN downregulation to stimulate angiogenesis in vitro. This contributed to enhanced wound healing and angiogenesis in streptozotocin-induced diabetic rats in vivo. Our results suggest that, in cell-free therapies, exosomes derived from DFO preconditioned stem cells manifest increased proangiogenic ability.

BackgroundMesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidate agents for treating critical-sized bone defects; they promote angiogenesis and may be an alternative to cell therapy. In this study, we evaluated whether exosomes derived from bone marrow-derived MSCs (BMSCs) preconditioned with a low dose of dimethyloxaloylglycine (DMOG), DMOG-MSC-Exos, exert superior proangiogenic activity in bone regeneration and the underlying mechanisms involved.MethodsTo investigate the effects of these exosomes, scratch wound healing, cell proliferation, and tube formation assays were performed in human umbilical vein endothelial cells (HUVECs). To test the effects in vivo, a critical-sized calvarial defect rat model was established. Eight weeks after the procedure, histological/histomorphometrical analysis was performed to measure bone regeneration, and micro-computerized tomography was used to measure bone regeneration and neovascularization.ResultsDMOG-MSC-Exos activated the AKT/mTOR pathway to stimulate angiogenesis in HUVECs. This contributed to bone regeneration and angiogenesis in the critical-sized calvarial defect rat model in vivo.ConclusionsLow doses of DMOG trigger exosomes to exert enhanced proangiogenic activity in cell-free therapeutic applications.

After spinal cord injury (SCI), destruction of the blood spinal cord barrier (BSCB) results in in ltration of blood cells, such as neutrophils and macrophages, leading to permanent neurological dysfunction.Previous studies have shown that human bone marrow mesenchymal stem cell (BMSC)-derived exosomes have a bene cial neuroprotective effect in SCI models. However, whether BMSC-Exos contribute to the integrity of the BSCB has not been clari ed. The purpose of this study was to investigate the mechanism of BMSC-Exo-induced changes in the permeability of the BSCB after SCI. Here, we showed that BMSC-Exos can inhibit BSCB permeability damage and improve spontaneous repair in a SCI model. Importantly, tissue inhibitors of matrix metalloproteinases 2 (TIMP2) were shown to play an important role in the functions of BMSCS-Exos by inhibiting the matrix metalloproteinase (MMP) pathway, thereby mitigating the reduction in cell junction proteins. Moreover, the ability of BMSC-Exos was signi cantly attenuated when TIMP2 was inhibited by siRNA. This proof-of-principle study demonstrates that BMSC-Exos can preserve the integrity of the BSCB and improve functional recovery after SCI through the TIMP2/MMP signaling pathway.