Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE−/- mice via miR-let7 mediated infiltration and polarization of M2 macrophage

Atherosclerosis is a chronic inflammatory disease of the vasculature. Exosomes derived from mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects; however, the MSCs-exosomes administration on atherosclerosis was unknown. Here, our ApoE-/- mice were fed a high-fat diet and received intravenous injections of exosomes from MSCs for 12 weeks. After tail-vein injection, MSCs-exosomes were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. MSCs-exosomes treatment decreased the atherosclerotic plaque area of ApoE-/- mice and greatly reduced the infiltration of macrophages in the plaque, associating induced macrophage polarization towards M2. In vitro, MSCs-exosomes treatment markedly inhibited LPS-induced M1 markers expression, while increased M2 markers expression in macrophages. Moreover, miR-let7 family was found to be highly enriched in MSCs-exosomes. Endogenous miR-let7 expression was found in the aortic root of ApoE-/- mice, and MSCs-exosomes treatment further up-regulated miR-let7 levels. In addition, inhibition of miR-let7 in U937 cells significantly inhibited the migration and M2 polarization via IGF2BP1 and HMGA2 pathway respectively in vitro. Our study demonstrates that MSCs-exosomes ameliorated atherosclerosis in ApoE-/- and promoted M2 macrophage polarization in the plaque through miR-let7/HMGA2/NF-κB pathway. In addition, MSCs-exosomes suppressed macrophage infiltration via miR-let7/IGF2BP1/PTEN pathway in the plaque. This finding extends our knowledge on MSCs-exosomes affect inflammation in atherosclerosis plaque and provides a potential method to prevent the atherosclerosis. Exosomes from MSCs hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases.