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

总结 心血管疾病（CVD）是全世界男性和女性死亡的主要原因， 然而，文献中的大量数据强调了男女之间的显著差异， CVD的发病率和严重程度。据观察，男性的心脏病进展更快， 随着年龄的增长，心肌质量的保存减少，年龄匹配的心肌收缩力更差 与女性相比。此外，女性面临的缺血性心脏并发症比年龄低- 在育龄期和绝经后年龄的男性中进行匹配。这些保护措施即使在 新生儿、青春期前和绝经后人群，这些人群的激素具有更大的同质性 男性和女性之间的差异表明，尽管性腺激素确实对不同的性别产生影响， 男女发病率之间的疾病过程中，有更多的等式。底层 除了女性性激素的公认作用外，造成这种性别差异的机制仍然存在 替补演员基于干细胞的疗法，特别是使用骨髓祖细胞的疗法， 作为缺血性组织修复的潜在新型治疗方法出现，然而， 现有的临床试验仍然不成比例地偏向于纳入男性患者（大约 80%男性受试者）。性别是否影响EPC/干细胞修复特性还不清楚 研究了然而，最近有证据表明，性别确实会影响大脑的功能。 干/祖细胞，尽管这种功能差异的机制知之甚少。我们 初步研究表明，来自雌性小鼠的骨髓内皮祖细胞（EPCs） 在缺血心脏的修复和血管生成方面，此外，我们的数据 表明这种功能二态性的分子基础部分取决于不同的表观遗传 来自不同性别的细胞中的景观似乎与性激素无关， 雌激素.因此，我们的中心假设是女性来源的BM-EPCs具有上级修复能力， 与男性相比，女性EPCs的功能优势涉及两者 雌激素依赖性和雌激素非依赖性信号传导和分子机制，包括差异 表观遗传景观该项目旨在详细研究，表型，表观遗传和分子基础， EPC修复性能的性别差异。这一总体目标将通过开展 本实验的目的有三：1）确定性别二态性的作用 2）阐明内皮祖细胞介导的心肌梗死后修复的表观遗传机制， 男性和女性EPC;以及3）测试性别特异性EPC衍生的外泌体的治疗功效， 心肌梗死后修复的无细胞模式。

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.