心脏流出道发育过程中的细胞命运转变及其调控机制

心脏流出道的发育过程包括形态发生和分隔发育。形态发生导致流出道扩展生长，为分隔发育建立基础，之后单一管道的流出道分隔成为主动脉和肺动脉根部，促进体循环和肺循环的建立。因此，流出道的形态发生和分隔发育对心血管发育和出生后存活至关重要。目前已知第二心场祖细胞在流出道发育过程中发挥关键作用：1. 贡献于流出道形态发生；2. 指导分隔发育。但其中的调控机制不甚明了。 我们围绕上述两个过程开展了系统性的研究工作，发现两种新的细胞命运转变形式：1. 第二心场祖细胞通过间充质到上皮转变(MET)贡献于流出道形态发生；2. 第二心场祖细胞来源的流出道心肌细胞可以转分化成为流出道内膜垫间充质细胞，参与分隔发育。以上两个细胞命运转变过程分别受Hand2及Baf155调控。在本申请中我们将对其中的调控机制进行深入探讨，阐述流出道发育过程中细胞命运转变的调控机理，开拓性地认识与理解胚胎时期的组织器官发育。

Cardiac outflow tract (OFT) development involves morphogenesis and septation. Morphogenic process results in OFT expansion growth that establishes the foundation for septation. OFT septation divides the single-tubular OFT into the roots of aorta and pulmonary artery, which facilitates the completion of systemic and pulmonary circulation. Therefore, OFT morphogenesis and septation is critical to cardiovascular development and post-natal survival. Currently, it is known that the second heart field (SHF) progenitors play a key role in OFT development: 1. Contribution to OFT morphogenesis; 2. Regulating OFT septation. Nonetheless, the underlying mechanisms are elusive. We have systematically investigated OFT morphogenesis and septation, and identified two types of cell fate transition: 1. The SHF progenitors contribute to OFT morphogenesis through mesenchymal to epithelial transition (MET); 2. The SHF-derived OFT cardiomyocytes can trans-differentiate into OFT cushion mesenchymal cells to control septation. The above mentioned two developmental processes are regulated by Hand2 and Baf155, respectively. In this proposal, we plan to make further detailed investigation of the regulatory mechanisms to uncover cell fate transition during OFT development. Results from this study will provide new insights for understanding organogenesis.