Abstract 101: Mesenchymal Stem Cells Attenuate Experimental Abdominal Aortic Aneurysm Formation via Inhibition of IL-17

Abstract

Objective: The immunomodulatory effects of mesenchymal stem cells (MSCs) remain to be defined in abdominal aortic aneurysm (AAA) formation. This study investigates the role of MSCs in the attenuation of AAA via inhibition of IL-17 using an in vivo elastase-perfusion murine model and by in vitro studies. Methods: AAAs were induced in 8- to 12-week old C57BL/6 (WT) mice using an elastase-perfusion (or heat inactivated elastase as control) AAA mouse model. The abdominal aorta was perfused for 5 minutes with 0.4 U/mL type 1 porcine pancreatic elastase. WT mice were also treated with MSCs (1x10 6 cells; intravenously) administered on day 1. On day 14 following perfusion, the abdominal aorta was measured by video micrometry and expressed as percentage increase over baseline aortic diameter. Cytokine analysis of aortic tissue was performed by multiplex-bead based ELISA. In vitro experiments evaluated cell proliferation and IL-17 production in mixed lymphocyte reactions with or without MSC treatment. Groups were compared using ANOVA followed by Bonferroni post hoc test. Results: A significant increase in aortic diameter was observed on day 14 in elastase-perfused WT mice compared to controls, which was significantly attenuated in the elastase-perfused WT mice treated with MSCs (141.1±16.2% vs 51.2±4.15% vs. 82.1±9.2%, respectively; p<0.05; n=6). A significant attenuation of pro-inflammatory cytokines/chemokines (IL-17, MCP-1, RANTES, IL-23, IFN-γ and TNF-α) production occurred in the aortic tissue from MSC-treated elastase-perfused WT mice compared to elastase-perfused WT mice on day 14. In vitro experiments demonstrated that activation of mononuclear cells (MNCs) by anti-human CD3 and CD28 resulted in significant cell proliferation compared to unstimulated MNCs, and was significantly suppressed by MSCs co-cultured with MNCs (18,323.2+882.2 vs. 1475.7+182.0 vs. 646.5+29.1 cpm, respectively; p<0.05; n=4). Furthermore, MSCs significantly attenuated IL-17 production by activated MNCs (163.5+27.8 vs. 1874.5+103.3 pg/ml, respectively; p<0.05; n=4). Conclusions: Mesenchymal stem cells attenuate AAA formation likely via mitigation of lymphocyte-produced IL-17 thereby offering a novel therapeutic strategy for treatment of aortic aneurysms.