MSC-derived sEVs enhance patency and inhibit calcification of synthetic vascular grafts by immunomodulation in a rat model of hyperlipidemia.

Vascular grafts often exhibit low patency rates in clinical settings due to the pathological environment within the patients requiring the surgery. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have attracted increasing attention. These sEVs contain many potent signaling molecules that play important roles in tissue regeneration, such as microRNA and cytokines. In this study, a sEVs-functionalized vascular graft was developed, and in vivo performance was systematically evaluated in a rat model of hyperlipidemia. Electrospun poly (ε-caprolactone) (PCL) vascular grafts were first modified with heparin, to enhance the anti-thrombogenicity. MSC-derived sEVs were loaded onto the heparinized PCL grafts to obtain functional vascular grafts. As-prepared vascular grafts were implanted to replace a segment of rat abdominal artery (1 cm) for up to 3 months. Results showed that the incorporation of MSC-derived sEVs effectively inhibited thrombosis and calcification, thus enhancing the patency of vascular grafts. Furthermore, regeneration of the endothelium and vascular smooth muscle was markedly enhanced, as attributed to the bioactive molecules within the sEVs, including vascular endothelial growth factor (VEGF), miRNA126, and miRNA145. More importantly, MSC-derived sEVs demonstrated a robust immunomodulatory effect, that is, they induced the transition of macrophages from a pro-inflammatory and atherogenic (M1) phenotype to an anti-inflammatory and anti-osteogenic (M2c) phenotype. This phenotypic switch was confirmed in both in vitro and in vivo analyses. Taken together, these results suggest that fabrication of vascular grafts with immunomodulatory function can provide an effective approach to improve vascular performance and functionality, with translational implication in cardiovascular regenerative medicine.