Background: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that mesenchymal stem cell (MSC)-derived microvesicles (MVs) can immunomodulate aortic inflammation to mitigate AAA formation and inhibit aortic smooth muscle cell (AoSMC) activation via modulation of microRNA-147.Methods and Results: An elastase-treatment model of AAA was used with 8- to 12- week old male C57BL/6 (WT) mice. Administration of MSCs or MVs in elastase-treated WT mice caused a significant attenuation of aortic diameter compared to elastase-treated mice alone. A significant mitigation of pro-inflammatory cytokines (IL-17, HMGB1, MCP-1, TNF-a; and KC), inflammatory cell (CD3+ T cells, macrophages and neutrophils) infiltration, increase in smooth muscle cell a-actin expression, and decrease in elastic fiber disruption occurred in aortic tissue from elastase-perfused mice treated with MSCs and MVs compared to elastase-treated mice alone. miRNA microarray analysis of murine aortic tissue demonstrated a significant upregulation of miR-147, a regulator of macrophage inflammatory responses, in elastase-treated mice compared to controls on day 14. MVs transfected with miR-147 mimic, but not with miR-147 inhibitor, attenuated HMGB1 secretion by elastase-treated human aortic explants and murine-derived CD11b+ macrophages. Similarly, treatment of AoSMCs with elastase or IL-17 induced pro-inflammatory cytokines (IL-6, RANTES, MCP-1, TNF-a and KC) which were attenuated by co-cultures with MVs transfected with miR-147 mimic, but not by miR-147 inhibitor.Conclusion: These results demonstrate that MSC-derived MVs attenuate aortic inflammation and inhibit macrophage and AoSMC activation via miR-147 suggesting a novel protective mechanism in AAA pathobiology.
|Effective start/end date||01/01/2017 → 12/31/2018|