Mesenchymal Stem Cell-Derived Nanovesicles as a Credible Agent for Therapy of Pulmonary Hypertension

Abstract

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.