Abstract P3093: Gender-specific Functional Dimorphism Of Bone Marrow Endothelial Progenitor Cells: Estrogen Independent Epigenetic Mechanisms

Several studies, including our labs, have previously determined the role of estrogen in augmenting EPC-based cardiac repair; however, a direct comparison of therapeutic efficacy of gender-specific stem cells or estrogen-independent mechanisms of gender-specific dimorphism in the reparative properties of BM-EPCs, has not been established. We hypothesized that epigenetic mechanisms contribute to the sex-specific functional dimorphism of Sca-1+/CD31+ BM-EPCs in regulating cell-homing, pro-angiogenic and anti-inflammatory functions in the ischemic myocardium leading to the enhanced reparative function of female EPCs. To evaluate our hypothesis, we sorted the male, female and ovariectomized (OVX) mice derived Sca-1+/CD31+ BM-EPCs using MACS multi-sort method. We then subjected the BM-EPCs through a series of cytokine quantifications and epigenetic screening followed by assessment of their therapeutic function and . Female and ovariectomized (OVX) female BM-EPCs secrete high levels of pro-angiogenic factors and low levels of pro-inflammatory cytokines compared to male BM-EPCs. Further evaluation of the secretome showed that the male EPCs secreted high levels of interleukins and chemokines compared to female and OVX EPCs. We found that male EPCs exclusively secreted CCL3/Mip-1α. Functional angiogenic evaluation of the EPC secretome showed higher propensity of female and OVX EPCs than the male EPCs. Post-MI injection of BM-EPCs resulted in remarkable preservation of cardiac structure and functions in both female BM-EPC groups compared to the male EPCs. Male EPC injection resulted in high inflammation in the heart tissue. Epigenetic sequencing of the BM-EPCs for the H3K9me3 mark showed high methylation in male EPCs compared to female and OVX EPCs. The inhibition of histone methyltransferase, Ehmt2/G9a using BIX-01294 upregulated the secretion of inflammatory factors in all EPCs. The conditioned medium from all EPCs with high levels of CCL3 inhibited angiogenesis . Neutralizing CCL3 in the same medium restored angiogenesis. Estrogen-independent epigenetic mechanisms govern the enhanced cardiac reparative properties of female BM-EPC.

Duke Scholars

Author Walter J. Koch Surgery, Cardiovascular and Thoracic Surgery