Manipulating bioactivities of endothelial progenitor cell-derived exosomes for promoting angiogenesis in ischemic vascular diseases

Exosomes paracrine-secreted by EPC (EPC-EXO) may exert strong pro-angiogenic effects, which offers a potential means to treat ischemic diseases. However, the mechanism of EPC-EXO-mediated angiogenesis remains unknown, and EPC-EXO shows poor homing to ischemic sites, which greatly limits the pro-angiogenic effect in vivo. We found that EPC-EXO from patients with coronary heart disease (C-EPC-EXO) was much less effective than EPC-EXO from healthy volunteers (H-EPC-EXO) in improving angiogenesis in murine hindlimb ischemia model. The miRNA sequencing and RT-PCR analyses detected abundant microRNA-199a-3p (miRNA-199a-3p) in C-EPC-EXO, and computational and luciferase reporter gene analyses further found that miR-199a-3p targeted the seed sequence of 4856–4862 in the 3′-untranslated region of RNA-binding protein Quaking isoform 5 (QKI-5) mRNA in 293T cells. Increasing the intracellular miR-199a-3p level of human umbilical vein endothelial cells (HUVECs) downregulated the QKI-5 gene expression and decreased angiogenesis, whereas inhibiting miR-199a-3p led to opposite results. Therefore, the miR-199a-3p-inhibited C-EPC-EXO promoted ECs-mediated angiogenesis more effectively than the original C-EPC-EXO. Besides, decorating C-EPC-EXO with cRGD enhanced targeting delivery to ischemic sites, further strengthening the pro-angiogenic effect of exosomes. Overall, manipulating the bioactivities of C-EPC-EXO through miR-199a-3p inhibition and cRGD decoration remarkably promotes ECs-mediated angiogenesis for treating ischemic vascular diseases.