MSC-derived sEVs enhance patency and inhibit calcification of synthetic vascular grafts by immunomodulation in a rat model of hyperlipidemia
MSC-derived sEVs enhance patency and inhibit calcification of synthetic vascular grafts by immunomodulation in a rat model of hyperlipidemia
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MSC 衍生的 sEV 通过免疫调节在高脂血症大鼠模型中增强合成血管移植物的通畅并抑制钙化
DOI：
10.1016/j.biomaterials.2019.01.049
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发表时间：
2019-06-01
期刊：
影响因子：
14
通讯作者：
Zhao, Qiang
中科院分区：
文献类型：
--
作者：
Wei, Yongzhen;Wu, Yifan;Zhao, Qiang
由于需要手术的患者体内的病理环境，血管移植在临床中往往表现出较低的通畅率。间充质干细胞（MSC）衍生的细胞外小泡（sev）越来越受到人们的关注。这些sev含有许多在组织再生中起重要作用的有效信号分子，如microRNA和细胞因子。在本研究中，我们开发了一种具有sev功能的血管移植物，并在高脂血症大鼠模型中系统地评估了其体内性能。首次采用肝素修饰电纺丝聚己内酯（PCL）血管，增强其抗血栓形成性。将msc来源的sev加载到肝素化PCL移植物上，以获得功能血管移植物。将制备好的血管移植物植入大鼠腹动脉一段（1cm），持续3个月。结果表明，mscs源性sev的掺入能有效抑制血栓形成和钙化，从而增强血管的通畅性。此外，由于sev中的生物活性分子，包括血管内皮生长因子（VEGF）、miRNA126和miRNA145，内皮和血管平滑肌的再生明显增强。更重要的是，msc衍生的sev显示出强大的免疫调节作用，即它们诱导巨噬细胞从促炎和致动脉粥样硬化（M1）表型转变为抗炎和抗成骨（M2c）表型。这种表型转换在体外和体内分析中都得到了证实。综上所述，这些结果表明，制造具有免疫调节功能的血管移植物可以提供一种有效的方法来改善血管的性能和功能，并在心血管再生医学中具有转化意义。
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 (epsilon-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.