The heart as a hemogenic organ

描述（由申请人提供）：哺乳动物生命期间发育的第一个功能器官系统是循环系统，由心管、大血管和造血组织组成。心管作为泵，甚至在有效的循环回路形成之前就开始跳动，背侧棘突作为导管，独立于心管形成，并在不久后连接到心管。这两个器官在结构和分子上是相似的，因为它们由外部肌肉层和内部内皮/内皮细胞层组成，并且每层表达许多共同的基因。因此，虽然来自发育上不同的起源，心管和背主动脉可能在其形成期间共享相似的遗传程序。循环系统的第三个组成部分，造血细胞，来自背主动脉的内皮细胞。这一过程与主动脉内皮的动脉特性密切相关，如动脉标志物的表达和心跳产生的生物力学力的影响。有趣的是，心管内的内皮细胞与主动脉内皮细胞共享所有这些分子和生理特性。在非哺乳动物和胚胎干细胞模型中，早期心脏祖细胞表达造血基因，并且心脏和造血谱系密切相关。在这个提议中，我们将研究心脏作为造血部位的发育作用。我们特别提出的特点的时空分布和多谱系分化潜力的假定生血细胞在形成endoepithelium（目的1），并检查Nkx2.5的作用，endoepithelium发展（目的2）。本提案的总体目标是测试心脏的生血活性。心脏的新作用和血细胞的隐藏来源的发现将显着提高我们对心血管造血发育程序的理解。临床上，髓外造血常见于心脏病和血液病患者。该项目将阐明这种临床病理疾病实体的发病机制。 公共卫生相关性：在发育和疾病背景下，心脏和造血谱系之间的密切关系已被提出，但心脏中造血程序的生物学意义仍不清楚。在这里，我们将揭示心脏作为造血器官的新作用。

DESCRIPTION (provided by applicant): The first functional organ system that develops during the mammalian life is the circulatory system, which consists of the heart tube, great vessels and hematopoietic tissues. The heart tube serves as the pump that starts to beat even before the formation of effective circulatory loop, and the dorsal aortae serve as conduits that form independently from the heart tube and link to it soon after. These two organs are structurally and molecularly similar in that they consist of outer muscular and inner endothelial/endocardial layers, and that each layer expresses many of the genes in common. Therefore, although derived from developmentally distinct origins, the heart tube and the dorsal aorta likely share similar genetic program during their formation. The third component of the circulatory system, the hematopoietic cells, arises from endothelial cells in dorsal aorta. This process is closely associated with the arterial identity of the aortic endothelium, such as the expression of arterial markers and the influence of biomechanical forces generated by the heartbeat. Interestingly, the endocardium in the heart tube shares all these molecular and physiological properties with aortic endothelilum. It has been suggested that the early cardiac progenitors express hematopoietic genes, and that cardiac and hematopoietic lineages are closely related in non-mammalian and embryonic stem cell models. In this proposal, we will examine the developmental role of the heart as a hematopoietic site. We specifically propose to characterize the spatiotemporal distribution and the multi-lineage differentiation potential of the putative hemogenic cells in the forming endocardium (Aim 1) and to examine the role of Nkx2.5 during the endocardial development (Aim 2). The overall goal of this proposal is to test the hemogenic activity of the heart. Discovery of a new role of the heart and a hidden source of blood cells will significantly enhance our understanding of the developmental program of cardio-vasculo-hematopoietic development. Clinically, extra-medullary hematopoiesis is often observed in patients with heart diseases and hematological disorders. The project will shed a light on the pathogenesis of this clinicopathological disease entity. PUBLIC HEALTH RELEVANCE: The close relationship between cardiac and hematopoietic lineages has been suggested in developmental and disease contexts, but it is still unclear the biological significance of the hematopoietic program in the heart. Here, we will uncover the novel role of the heart as a hemogenic organ.