The heart as a hemogenic organ

描述（申请人提供）：哺乳动物生命中发育的第一个功能器官系统是循环系统，它由心管、大血管和造血组织组成。心管作为泵，在有效循环回路形成之前就开始跳动；背主动脉作为导管，独立于心管形成，随后与心管相连。这两个器官在结构和分子上是相似的，因为它们由外肌层和内内皮/心内膜层组成，而且每一层都表达许多共同的基因。因此，尽管心管和背主动脉的起源不同，但它们在形成过程中可能具有相似的遗传程序。造血细胞是循环系统的第三个组成部分，起源于主动脉背侧的内皮细胞。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，心管中的心内膜与主动脉内皮具有所有这些分子和生理特性。研究表明，早期心脏祖细胞表达造血基因，在非哺乳动物和胚胎干细胞模型中，心脏和造血谱系密切相关。在这个建议中，我们将研究心脏作为造血部位的发育作用。我们特别提出表征心内膜形成过程中假定的造血细胞的时空分布和多谱系分化潜力（目的1），并研究Nkx2.5在心内膜发育过程中的作用（目的2）。这项建议的总体目标是测试心脏的血液生成活动。发现心脏的新作用和隐藏的血细胞来源将大大提高我们对心血管造血发育的理解。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。

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.