Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147

Abstract

The formation of an abdominal aortic aneurysm (AAA) is characterized by inflammation, macrophage infiltration, and vascular remodeling. In this study, we tested the hypothesis that mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) immunomodulate aortic inflammation, to mitigate AAA formation via modulation of micro RNA-147. Anelastase-treatment model of AAA was used in male C57BL/6wild-type (WT) mice. Administration of EVs in elastase-treated WT mice caused a significant attenuation of aortic diameter andmitigated proinflammatorycytokines, inflammatorycell infiltration, anincrease insmoothmuscle cella-actin expression, and a decrease in elastic fiber disruption, compared with untreatedmice. A 10-fold up-regulation of microRNA (miR)- 147, a keymediator ofmacrophage inflammatory responses, was observedinmurine aortic tissue in elastase-treated mice compared with control sond 14. EVs derived from MSCs transfected with miR-147 mimic, but not with miR-147 inhibitor, attenuated aortic diameter, inflammation, and leukocyte infiltration in elastase-treated mice. In vitro studies of human aortic tissue explants and murine-derived CD11b+ macrophages induced proinflammatory cytokines after elastase treatment, and the expressionwas attenuated by cocultureswith EVs transfectedwith miR-147 mimic, but notwithmiR-147 inhibitor. Thus, our findings define a critical role ofMSC-derivedEVs inattenuation of aortic inflammation and macrophage activation via miR-147 during AAA formation.