Integrin a5调节第二心场细胞极性从而影响其细胞分化过程中命运选择的机制研究

The second heart field contribute cells to the outflow tract and differentiate into myocytes, smooth muscles and endothelial cells. Abnormal addition and differentiation of second heart field cells would leads to the shortage of outflow tract and congenital conotruncal defects at later stages. However, little is known about the fate choice mechanisms during the second heart field cell differentiation. Our previous publication shows that Integrin α5 is required for the second heart field cell contribution to the outflow tract. Further studies show that Integrin α5 is very important for the cell polarity of second heart field cells. The loss of Integrin α5 in the second heart field cells increases Wnt signaling and causes abnormal differentiation toward the endothelial cell lineage at the expense of cardiomyocytes. All these findings suggest that Integrin α5 is essential for second heart field differentiation and outflow tract development.

第二心场细胞可增殖分化为心肌细胞、血管平滑肌细胞和血管内皮细胞等。其发育缺陷可造成胚胎早期心脏流出道变短，导致以大动脉及分支动脉形态、位置异常为特征的先天性心脏圆锥动脉干畸形。但是第二心场细胞在分化过程中的命运选择机制仍不明确。我们已经报道过，细胞粘附分子Integrin α5调节第二心场细胞对心脏流出道的贡献。本课题进一步研究发现，Integrin α5维持和建立第二心场细胞的极性。Integrin α5的缺失引起第二心场细胞Wnt信号通路上调，导致细胞分化从心肌细胞向血管内皮细胞方向偏移。本研究旨在明确Integrin α5调节第二心场前体细胞分化过程中命运选择的机制，揭示心脏流出道正常形态发育的重要过程，从而为心脏圆锥动脉干畸形这类先天性心脏病的发生机制提供新的理论依据。

细胞-细胞外基质的相互作用是发育生物学、肿瘤生物学的热点课题。本研究发现 Fibronectin-Integrin介导的细胞-细胞外基质的相互作用对神经嵴细胞调节心血管、头面部的器官形成：1. Fibronectin-Integrin介导的细胞-细胞外基质的相互作用对心血管流出道的发育过程至关重要；2. Fibronectin-Integrin介导的细胞-细胞外基质的相互作用对头面部器官发育非常必要；3. 神经嵴细胞分泌的Fibronectin通过调节BMP/SHH信号传导通路，对小鼠胚胎的甲状旁腺和胸腺的发育起着至关重要的作用。.本课题明确了Fibronectin-Integrin介导的细胞-细胞外基质在神经嵴细胞调节器官形成中的重要作用。