哺乳动物心脏心内膜的造血潜能及其机制调控研究

心脏驻留型巨噬细胞在心脏稳态维持及损伤修复中发挥重要作用，探索并揭示心脏巨噬细胞的发育起源及其分子机制意义重大。科学界主流观点认为小鼠胚胎期心脏巨噬细胞主要起源于卵黄膜（YS）和主动脉-性腺-中肾（AGM）区的生血内皮。近期有研究报道心内膜也属于生血内皮，可以贡献给大量的心脏巨噬细胞并能参与心脏瓣膜重塑。然而，我们前期工作基础发现前人使用的心内膜遗传工具在标记心内膜的同时还标记了YS和AGM生血内皮，所以心内膜是否具有造血潜能依然存在争议，产生争议的主要原因是遗传工具的不特异性。本项目中我们将建立心内膜特异性遗传示踪技术，通过严格的谱系示踪实验来揭示心内膜是否具有造血能力及其潜在的调控机制，并通过建立新遗传工具对YS和AGM生血内皮贡献心脏巨噬细胞进行重新检测。综上，本项目将帮助我们明确心内膜是否具有造血活性以及心脏巨噬细胞的发育起源，这将为心脏发育及心脏疾病的临床治疗提供新的理论基础。

Cardiac resident macrophages play essential roles in the maintenance of cardiac homeostasis and cardiac healing after injury. It is of great significance to explore and reveal the developmental origin and it regulatory mechanism of cardiac macrophages. The mainstream view holds that cardiac macrophages of embryonic mouse are mainly originated from two types of hemogenic endothelium (HE) with hematopoietic activity: yolk sac (YS) endothelium and aorta-gonad-mesonephros (AGM) endothelium. However, recent studies have found that the heart endocardium also belongs to HE and can contribute to a large number of cardiac resident macrophages, which are essential for valvular remodeling. However, based on our previous work, we found that the endocardial genetic tools used by predecessors not only marked the endocardium but also marked YS and AGM hemogenic endothelium. Therefore, whether the endocardium has hematopoietic potential remains controversial. The main reason for the above controversy is the non-specificity of genetic tools. In this project, we will establish the endocardium-specific genetic tracing technology, through rigorous lineage tracing experiments to reveal whether the endocardium has hematopoietic ability and its potential regulation mechanism, and establish new genetic tools to reinvestigate the contributions of YS and AGM hemogenic endothelium to cardiac macrophages. In summary, this project will help us clarify whether the endocardium has hematopoietic activity and the developmental origin of cardiac macrophages, which will provide a new theoretical basis for cardiac development and clinical treatment of cardiac diseases.