LAUSR

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have been evaluated in many studies as promising therapeutic agents for pulmonary hypertension (PH). However, low yields and heterogeneity are a major barrier in the translational utility of EVs for clinical studies. To address these limitations, we fabricated MSCs derived nanovesicles (MSC-NVs) by serial extrusion through filters resulting in MSC-NVs with characteristics similar to conventional EVs but with much higher production yields. Herein, we examined the therapeutic efficacy of MSC-NVs in preclinical models of PH in vitro and in vivo. Intervention with MSC-NVs improved the core pathologies of monocrotaline (MCT) induced PH in rat. Intravenous administration of MSC-NVs resulted in significant uptake within hypertensive lungs, pulmonary artery lesions and especially in pulmonary artery smooth muscle cells (PASMCs). In vitro, MSC-NVs inhibited PDGF-induced proliferation, migration, and phenotype switch of PASMCs. miRNA sequencing analysis of the genetic cargo of MSC-NVs revealed that miR-125b-5p and miR-100-5p are highly abundant, suggesting they might account for the therapeutic effects of MSC-NVs in PH. Depletion of miR-125b-5p and miR-100-5p in MSCs almost completely abolished the beneficial effects of MSC-NVs in protecting PASMCs from PDGF stimulated changes in vitro, and also diminished the protective effects of MSC-NVs in MCT induced PH in vivo. These data highlight the efficacy and advantages of MSC-NVs over MSC-EVs as a promising therapeutic strategy against PH.