J. P. Davis1, M. Salmon1, N. Pope1, G. Lu1, A. Meyer1, G. Su1, G. Ailawadi1, G. R. Upchurch1 1University Of Virginia,Surgery,Charlottesville, VA, USA
Introduction:
As no medical therapies are yet available to slow abdominal aortic aneurysm (AAA) growth, this study sought to investigate the effect of different genders of bone marrow derived mesenchymal stem cells (MSCs) on AAA growth in a murine AAA model. Given the decreased rate of AAA in women, it is hypothesized that female MSCs would attenuate AAA growth more so than male MSCs.
Methods:
Aortas of 8- to 10-week-old male C57Bl/6 mice were perfused with purified porcine pancreatic elastase (0.35 units/ml) to induce AAA formation. MSCs were harvested from bone marrow of femurs of 7- to 8-week-old male and female C57Bl/6 mice and male and female red fluorescent protein homozygous mice (RFP+/+) and isolated using standard protocols. MSCs from male and female mice were dosed via tail vein injection (3 million cells per dose, 500 µL of volume per injection) on post-aortic perfusion days 1, 3, and 5. Aortas were harvested after 14 days. Video micrometry was used to measure AAA phenotypic characteristics. Fluorescent staining was performed on aortic tissue and evaluated with confocal microscopy. Cytokine arrays were performed on aortic tissue. Groups were compared using an ANOVA and a Tukey’s post hoc test.
Results:
Mean aortic dilation in the elastase group was 121±13.8% (mean±SD), while male MSC inhibited AAA growth (*87.8±22.8%, P=0.0014) compared to elastase. However, female MSCs showed the most marked attenuation of AAA growth when compared to elastase (**75.2±25.9% P= 0.0008, Figure). Convergence of confocal microscopy channels revealed RFP+/+ MSCs of both genders integrated within the aortic wall. Tissues treated with either male or female MSCs revealed significantly decreased levels of Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)(males p=0.0011, females p=0.0003 compared to elastase) and Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) (males p=0.003, females p<0.0001 compared to elastase). Pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and macrophage chemotactic protein-1 (MCP-1) were only decreased in tissues treated with female MSCs (p=0.001, p=0.01, and p<0.001, respectively when compared to elastase).
Conclusions:
These data document that MSCs attenuate AAA growth in the murine model, and MSCs integrate into the aortic wall after treatment. Furthermore, female MSCs and male MSCs inhibit proinflammatory cytokines at varying levels. The effects of MSCs on aortic tissue offer a promising insight into biologic therapies for future medical treatment of AAAs in humans.
