Sex-Based Differences in Vascular Repair With Bone Marrow Cell Therapy: Relevance of Regulatory and Th2-type Cytokines

Objectives: There are differences in symptoms, risk stratification, and efficacy of pharmacological treatments between men and women with coronary artery disease (CAD). The results of clinical studies of cell therapy in CAD patients are mixed. The relevance of sex to response to cell therapy is unknown. We investigated sex-based differences in response to bone marrow mononuclear cells (BM-MNCs) in atherosclerotic apoliproprotein E-knockout (ApoE^-/-) mice. Methods: Twenty-three male and 27 female ApoE^-/- mice fed on a high-fat diet received four intravenous BM-MNC injections (C57BL6/J mice) starting at 14 weeks of age; male or female BM-MNCs were administered. Thirteen male and 20 female atherosclerotic ApoE^-/- mice received vehicle. Aortic plaque burden (%), recipient bone marrow progenitor cell profiles (FACS-LSR II, FlowJo) and 22 circulating cytokine panel (LINCOplex) were quantified and analyzed statistically (SSPS, P ≤ .05). Results: Quantitative and semiquantitative results are presented. Increased G-CSF levels correlated with plaque reduction (r = -.86, P = .0004). G-CSF was clustered with IL-15. Conclusions: Female but not male BM-MNCs exhibited atheroprotection in male atherosclerotic ApoE^-/- mice. Plaque lesions did not attenuate atherosclerosis in female ApoE^-/- mice with BM-MNCs of either donor sex. An increase in regulatory and in Th2-type response may be required for atheroprotection. Sex-based differences in vascular repair have implications for cell therapy trials in CAD.