Nano-Sized Extracellular Vesicles Secreted from GATA-4 Modified Mesenchymal Stem Cells Promote Angiogenesis by Delivering Let-7 MiRNAs

We demonstrated previously that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) play a critical role in angiogenesis. Here, we examine whether this pro-angiogenic efficacy is enhanced in EVs derived from MSCs overexpressing GATA-4 (MSC). Methods and Results. EVs were isolated from MSC (EV) and control MSCs transduced with an empty vector (EV). EVs from both cell types were of the same size and displayed similar molecular markers. Compared with EV, EV increased both a tube-like structure formation and spheroid-based sprouting of human umbilical vein endothelial cells (HUVECs). The EV increased the numbers of CD31-positive cells and hemoglobin content inside Matrigel plugs subcutaneously transplanted into mice for 2 weeks. Moreover, EV encapsulated higher levels of let-7 family miRs compared to EV. The transfer of exosomal let-7 miRs into HUVECs was recorded with an accompanied down-regulation of thrombospondin-1 (THBS1) expression, a major endogenous angiogenesis inhibitor. The loss-and-gain of function studies of let-7 miRs showed that let-7f knockdown significantly decreased EV-mediated vascularization inside Matrigel plugs. In contrast, let-7f overexpression promoted HUVEC migration and tube formation. Conclusion. Our results indicate that EVs derived from genetically modified MSCs with GATA-4 overexpression had increased pro-angiogenic capacity due to the delivery of let-7 miRs that targeted THBS1 in endothelial cells.