1 Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
2 Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
Cell Transplant. 2018 Jul;27(7):1080-1095. doi: 10.1177/0963689718780942. Epub 2018 Jun 28.
Extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) mediate their paracrine effect, but their efficacy to protect the microcirculation of the kidney is unknown. Using a novel swine model of unilateral renovascular disease (RVD) complicated by metabolic syndrome (MetS), we tested the hypothesis that EVs would attenuate renal microvascular loss.
Four groups of pigs ( n = 7 each) were studied after 16 weeks of diet-induced MetS and RVD (MetS+RVD), MetS+RVD treated 4 weeks earlier with a single intra-renal delivery of EVs harvested from autologous adipose tissue-derived MSCs, and Lean and MetS Sham controls. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo (fast CT), whereas EV characteristics, renal microvascular architecture (micro-CT), and injury pathways were studied ex-vivo.
mRNA sequencing and proteomic analysis revealed that EVs are packed with several pro-angiogenic genes and proteins, such as vascular endothelial growth factor. Labeled EVs were detected in the stenotic kidney 4 weeks after injection internalized by tubular and endothelial cells. EVs restored renal expression of angiogenic factors and improved cortical microvascular and peritubular capillary density. Renal apoptosis, oxidative stress, tubular injury, and fibrosis were also attenuated in EV-treated pigs. RBF and GFR decreased in MetS+RVD compared with MetS, but normalized in MetS+RVD+EVs.
Intra-renal delivery of MSC-derived EVs bearing pro-angiogenic properties restored the renal microcirculation and in turn hemodynamics and function in chronic experimental MetS+RVD. Our study suggests a novel therapeutic potential for MSC-derived EVs in restoring renal hemodynamics in experimental MetS+RVD.
间充质干细胞（MSCs）释放的细胞外囊泡（EVs）介导其旁分泌作用，但它们保护肾脏微循环的功效尚不清楚。使用一种新的单侧肾血管疾病（RVD）合并代谢综合征（MetS）的猪模型，我们检验了 EVs 会减轻肾脏微血管丢失的假说。
4 组猪（每组 7 只）在饮食诱导的 MetS 和 RVD（MetS+RVD）后 16 周、MetS+RVD 早期用单次肾内注射源自自体脂肪组织衍生的 MSC 的 EV 治疗、以及瘦素和 MetS 假手术对照组进行研究。肾血流（RBF）和肾小球滤过率（GFR）通过体内快速 CT 测量，而 EV 特征、肾脏微血管结构（微 CT）和损伤途径则通过体外研究。
mRNA 测序和蛋白质组学分析表明，EVs 中含有多种促血管生成基因和蛋白，如血管内皮生长因子。注射后 4 周，标记的 EVs 在狭窄肾脏中被检测到，并被肾小管和内皮细胞内化。EVs 恢复了肾脏中血管生成因子的表达，并改善了皮质微血管和肾小管周围毛细血管密度。EV 治疗的猪的肾细胞凋亡、氧化应激、肾小管损伤和纤维化也减轻。与 MetS 相比，MetS+RVD 中的 RBF 和 GFR 降低，但在 MetS+RVD+EVs 中恢复正常。
肾内注射具有促血管生成特性的 MSC 衍生 EVs 恢复了慢性实验性 MetS+RVD 中的肾脏微循环，进而恢复了血液动力学和功能。我们的研究表明，MSC 衍生 EVs 在恢复实验性 MetS+RVD 中的肾脏血液动力学方面具有潜在的新治疗方法。
