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

摘要 心血管疾病(CVD)是全世界男性和女性死亡的主要原因， 然而，来自文献的大量数据强调了男女之间在以下方面的显著差距 脑血管病的发生率和严重程度。据观察，男性的心脏进展更快。 衰竭，随着年龄增长，心肌质量保存较差，与年龄匹配的心肌收缩能力较差 与女性相比。此外，与年龄相比，女性患缺血性心脏病的风险更低。 在生育年龄和绝经后年龄都与男性相匹配。这些保护即使在 激素同质性较高的新生儿、青春期前和绝经后人群 男性和女性之间的差异表明，尽管性腺激素确实对不同的 除了男性和女性之间疾病过程的发病率，等式中还有更多的因素。潜在的 造成这种性别差异的机制仍然存在，这超出了女性性激素的公认影响 未得到充分研究。以干细胞为基础的疗法，特别是那些使用骨髓祖细胞的疗法，具有 作为一种潜在的新的治疗方法出现在缺血组织修复中，然而患者群体 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%的男性受试者)。性别是否影响EPC/干细胞修复特性一直不是很好 学习。然而，最近开始有证据表明，性别确实影响大脑的功能。 干细胞/祖细胞，尽管对这种功能差异的机制知之甚少。我们的 初步研究表明，雌性小鼠的骨髓内皮祖细胞(EPC) 在缺血心脏的修复和血管生成方面比雄性小鼠更有效。此外，我们的数据 表明这种功能二型性的分子基础部分取决于不同的表观遗传学。 不同性别细胞中的景观似乎不受性激素的影响，包括 雌激素。因此，我们的中心假设是女性来源的BM-EPC具有更好的修复能力 女性EPC在功能上优于男性EPC 雌激素依赖和雌激素非依赖性信号和分子机制，包括差异 表观遗传景观。本项目的目的是详细研究银屑病的表型、表观遗传学和分子基础。 EPC修复性属性的性别差异。这一总体目标将通过开展 在以下三个具体目标下组织的实验：1)确定性别二态的作用 EPC介导的心肌梗死后修复；2)阐明心肌梗死后功能差异的表观遗传学机制 男性和女性EPC；以及3)测试性别特异性EPC来源的Exosome的治疗效果，如 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.