CAR (CARSKNKDC) Peptide Modified ReNcell-Derived Extracellular Vesicles as a Novel Therapeutic Agent for Targeted Pulmonary Hypertension Therapy

作者：Jie Wang, Li Hu, Huijie Huang, Yanfang Yu, Jingshen Wang, Youjia Yu, Kai Li, Yan Li, Tian Tian, Feng Chen · 发表于：Hypertension · 年份：2020 · DOI：10.1161/hypertensionaha.120.15554 · 被引用次数：30 · 研究领域：Pulmonary Hypertension Research and Treatments、Extracellular vesicles in disease、Circular RNAs in diseases

In recent years, mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are emerging as a potential therapeutic agent for pulmonary hypertension (PH). However, the full realization of MSCs-derived EVs therapy has been hampered by the absence of standardization in MSCs culture and the challenges of industrial scale-up. The study was to exploit an alternative replacement for MSCs using currently commercialized stem cell lines for effective targeted PH therapy. ReNcell VM-a human neural stem cell line-has been utilized here as a reliable and easily adoptable source of EVs. We first demonstrated that ReNcell-derived EVs (ReNcell-EVs) pretreatment effectively prevented Su/Hx (SU5416/hypoxia)-induced PH in mice. Then for targeted therapy, we conjugated ReNcell-EVs with CAR (CARSKNKDC) peptide (CAR-EVs)-a peptide identified to specifically target hypertensive pulmonary arteries, by bio-orthogonal chemistry. Intravenous administration of CAR-EVs selectively targeted hypertensive pulmonary artery lesions especially pulmonary artery smooth muscle cells. Moreover, compared with unmodified ReNcell-EVs, CAR-EVs treatment significantly improved therapeutic effect in reversing Su/Hx-induced PH in mice. Mechanistically, ReNcell-EVs inhibited hypoxia-induced proliferation, migration, and phenotype switch of pulmonary artery smooth muscle cells, at least in part, via the delivery of its endogenous highly expressed miRNAs, let-7b-5p, miR-92b-3p, and miR-100-5p. In addition, we also ...