Project 2: Gender Dimorphism in Bone Marrow Endothelial Progenitor Cell-mediated Post-Infarct Myocardial Repair

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Summary Cardiovascular disease (CVD) is a leading cause of mortality across the world in both men and women, however, abundant data from the literature underscore a significant disparity between men and women for the incidence and severity of CVD. It has been observed that men undergo more rapid progression of heart failure, less preservation of myocardial mass as they age, and worse age-matched cardiac contractility compared to women. Moreover, women are exposed to a lower ischemic heart complication than age- matched men both in the reproductive and postmenopausal age. These protection remain present even in neonatal, prepubescent and postmenopausal populations where there is greater homogeny of hormones between males and females indicating that although gonadal hormones do have an impact on differing incidences of disease processes among men and women, there is more to the equation. The underlying mechanisms responsible for this gender disparity beyond recognized effects of female sex hormones remain understudied. Stem cell-based therapies, particularly those employing bone marrow progenitors, have emerged as a potential novel therapeutic approach in ischemic tissue repair however patient population for available clinical trials remain disproportionately biased towards inclusion of male patients (approximately 80% male subjects). Whether gender influences EPC/stem cell reparative properties has not been well studied. Recently however, evidence has begun to emerge that gender does influence the functionality of stem/progenitor cells, although mechanisms for such functional disparity are poorly understood. Our preliminary studies indicate that bone marrow endothelial progenitor cells (EPCs) from female mice are more efficient than those from male mice in the repair and angiogenesis in ischemic heart. Additionally, our data indicates that molecular basis of this functional dimorphisms partly depends upon different epigenetic landscape in cells from different genders which appears to be independent of sex hormones including estrogen. Therefore our central hypothesis is that female derived BM- EPCs possess superior reparative properties than their male counterparts and that functional superiority of female EPCs involves both estrogen-dependent and estrogen-independent signaling and molecular mechanisms including a differential epigenetic landscape. This project aims to study, in detail, phenotypic, epigenetic and molecular basis of gender-specific differences in EPC reparative properties. This overall aim will be achieved by conducting experiments organized under the following three specific aims: 1) To determine the role of gender dimorphism on EPC -mediated post-MI repair; 2) To elucidate epigenetic mechanisms of functional disparity between male and female EPCs; and 3) To test the therapeutic efficacy of gender specific-EPC- derived exosomes as cell-free modality for post-MI repair.