Abstract
Introduction: Stem cell-derived extracellular vesicles (EVs) are known to facilitate cell-to-cell communication. The potential of mesenchymal stem cell (MSC)-derived EVs for cardiac repair when compared with MSC whole cell injection remains unknown. Hypothesis: We hypothesized that therapy with MSC-EVs after a reperfused myocardial infarction (MI) will result in greater improvement in LV structure and function compared with injection of MSCs. Methods: EVs were collected by sequential centrifugation from culture supernatants of murine bone marrow MSCs. We used tunable resistive pulse sensing technology (TRPS), flow cytometry, real-time qRT-PCR and mass spectrometry to analyze MSC-EVs. Wild-type (C57BL/6) mice underwent a 30-min coronary occlusion followed by reperfusion, and 48 h later received intramyocardial injection of vehicle (PBS, n=14), MSCs (n=14), or MSC-EVs (n=14). Echocardiography was performed 4 d prior to MI (BSL) and at 48 h and 30 d after injection. Mice were sacrificed after 30 d. Results: MSC-EVs were noted to be small vesicles with average size of 233.0 ± 70.2 nm (Fig), and expressed MSC-specific markers, including CD29, CD90.2, CD105, Sca-1 and CD49e (Fig). MSC-EVs were enriched in mRNAs, miRNAs and proteins from donor MSCs; and carried transcripts of genes regulating cardiac/vascular differentiation, such as GATA-4, Nkx2.5, Tie-2, and GATA-2. In vivo, LV ejection fraction (EF) was significantly and similarly reduced in all groups at 48 h after MI (Fig). At 30 d after MI, mice injected with MSC-EVs exhibited significantly higher EF (Fig) and smaller LV end-diastolic volume compared with vehicle-treated and MSC-injected mice. Conclusions: We conclude that MSC-EVs represent natural nanocarriers capable of transferring bioactive contents and inducing cardiac repair following intramyocardial injection after MI in vivo. The use of MSC-EVs may potentially improve the outcomes of cell therapy in humans.
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