Hemogenic endocardium: contribution to the valvular tissue macrophages

 描述(申请人提供)：心脏、血管和造血的发展是相互联系的。造血细胞不仅仅是被动地通过循环系统运输的乘客，而且实质上参与了器官的发育和修复。通过先例R21建议，我们已经确定心内膜细胞产生造血细胞。这些造血性心内膜细胞在小鼠胚胎的垫状心内膜中得到丰富，并通过Nkx2-5依赖的方式进行心内膜向造血细胞的转化。这一机制在物种之间是保守的。然而，由于心内膜来源的造血细胞很少对骨髓中的出生后造血干细胞系统做出贡献，这一发现的生物学意义受到了阻碍。一个基本的问题是，为什么心脏需要在这个特定的阶段在这个特定的区域产生造血细胞。这个问题的答案需要彻底了解血源性心内膜的分子机制和细胞分化。这一建议利用特定的遗传标记工具来建立一个关键的Nkx2-5-Notch-RUNX1途径，一个新的组织巨噬细胞群，起源于血液来源的心内膜细胞，以及以前未被认识到的心内膜来源组织巨噬细胞在心脏瓣膜形成中的作用。综上所述，这一建议将对血源性心内膜具有生物学意义，并表明血源性心内膜不仅是像盲肠一样的系统发育残留物，而且是在器官功能中发挥重要作用的不可或缺的组成部分。在美国，先天性瓣膜异常影响1-2%的活产儿，具有遗传倾向的患者更有可能发展为与年龄相关的瓣膜缺陷。如果获得资金，这项提案将延长我们的发现 从血源性心内膜到一种新的先天性心脏瓣膜畸形的发病机制。

 DESCRIPTION (provided by applicant): The development of cardiac, vascular and hematopoietic is mutually linked. The hematopoietic cells are not just passengers passively transported through the circulatory system, but substantially involved in the development and repair of the organs. Through the precedent R21 proposal, we have established that endocardial cells give rise to hematopoietic cells. These hemogenic endocardial cells are enriched in the cushion endocardium in mouse embryos and undergo endocardial-hematopoietic transition via Nkx2-5- dependent manner. This mechanism is conserved among species. However, biological significance of this discovery has been hampered by the fact that the endocardially-derived hematopoietic cells rarely contribute to the postnatal hematopoietic stem cell system in the bone marrow. A fundamental question is why the heart needs to generate hematopoietic cells in this specific region at this specific stage. Answer to this questio requires thorough understanding of the molecular mechanism and cellular differentiation of the hemogenic endocardium. This proposal take advantage of specific genetic labeling tool to establish a pivotal Nkx2-5- Notch-Runx1 pathway, a novel tissue macrophage population originating from hemogenic endocardial cells, and a previously unappreciated role of endocardially-derived tissue macrophages in the formation of the cardiac valves. Together, this proposal will provide a biological significance to hemogenic endocardium, and demonstrate that the hemogenic endocardium is not merely a phylogenetical remnant like intestinal cecum but an indispensable component that plays a significant role in the organ function. Congenital valvular anomaly affects 1-2% of live births in the U.S., and patients with genetic predisposition are more likely to develop age- related valvular defects. If funded, this proposal will extend our discovery of hemogenic endocardium to a novel disease mechanism of congenital valvular anomalies.