染色质重塑复合物在心脏祖细胞发育过程中的作用和机制

During early heart development, two populations of cardiac progenitor cells are specified from mesoderm and termed the first heart field (FHF) progenitors and the second heart field (SHF) progenitors. The FHF progenitors contribute to the development of left ventricle and left/right atria , while the SHF progenitors develop to the right ventricle, outflow tract (OFT) as well as part of the left/right atria. The SHF progenitor development involves cell proliferation, differentiation and migration, in which the epigenetic regulatory mechanisms are not well understood. Supported by previous project, we have identified the important role of BAF155, a critical subunit of the chromatin-remodeling complex in the SHF progenitor development. Deletion of BAF155 in the SHF progenitors gives rise to severe OFT defects, including PTA and DORV, which suggests that BAF155 is essential for OFT separation and alignment. The interaction among the SHF, cardiac neural crest cells and endothelial cells determines OFT separation and alignment. In this proposal, we will investigate the regulatory mechanisms of BAF155 in OFT development in order to understand the function of the chromatin-remodeling complex in SHF progenitor and OFT development. This study will help elucidate heart developmental defects.

在早期心脏发育过程中，两群心脏祖细胞由中胚层特化形成，分别称为第一心场祖细胞和第二心场祖细胞。第一心场祖细胞主要贡献于左心室和左右心房，第二心场祖细胞贡献于右心室，流出道和部分左右心房。第二心场祖细胞的发育涉及细胞增殖，分化和迁移，其中的表观遗传调控机制不甚明了。我们在前期培育项目研究中发现：染色质重塑复合物重要组成亚单位BAF155在第二心场发育过程中发挥重要的作用，在第二心场祖细胞中将其剔除后引起严重的流出道发育畸形，包括永存动脉干（PTA)及右室双流出道（DORV),表明BAF155在流出道分割和排列发育过程中起至关重要的作用。流出道分割和排列发育过程涉及第二心场,神经嵴细胞及内皮细胞的相互作用，我们拟对其中的分子和细胞生物学调控机制进行深入研究，以期阐明染色质重塑复合物在第二心场祖细胞发育过程中的功能和调控机制，理解流出道发育过程和对心脏发育异常的认识。

利用模式动物小鼠，分别在心脏流出道的三种组成细胞-心肌细胞，神经嵴细胞及内皮细胞中剔除SWI/SNF染色质重塑复合物重要组成成员Baf155，分析流出道发育过程。发现在流出道心肌细胞（第二心场来源）及神经嵴细胞中剔除Baf155，均导致流出道不能分割，产生永存动脉干（persistent truncus arteriosus, PTA）表型，提示BAF155通过调控流出道心肌及神经嵴细胞发育从而参与调控流出道分割。在流出道内皮细胞中剔除Baf155，导致早期胚胎致死，无法观察流出道分割状况。.初步探讨了BAF155调控流出道机制。.这是一个一年期项目，后续工作继续进行中。