Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030-3303, USA.
Circ Res. 2010 Nov 12;107(10):1209-19. doi: 10.1161/CIRCRESAHA.110.225318. Epub 2010 Sep 16.
Heart valves develop from precursor structures called cardiac cushions, an endothelial-lined cardiac jelly that resides in the inner side of the heart tube. The cushions are then invaded by cells from different sources, undergo a series of complicated and poorly understood remodeling processes, and give rise to valves. Disruption of the fibroblast growth factor (FGF) signaling axis impairs morphogenesis of the outflow tract (OFT). Yet, whether FGF signaling regulates OFT valve formation is unknown.
To study how OFT valve formation is regulated and how aberrant cell signaling causes valve defects.
By using mouse genetic manipulation, cell lineage tracing, ex vivo heart culture, and molecular biology approaches, we demonstrated that FGF signaling in the OFT myocardium upregulated Bmp4 expression, which then enhanced smooth muscle differentiation of neural crest cells (NCCs) in the cushion. FGF signaling also promoted OFT myocardial cell invasion to the cushion. Disrupting FGF signaling interrupted cushion remodeling with reduced NCCs differentiation into smooth muscle and less cardiomyocyte invasion and resulted in malformed OFT valves.
The results demonstrate a novel mechanism by which the FGF-BMP signaling axis regulates formation of OFT valve primordia by controlling smooth muscle differentiation of cushion NCCs.
心脏瓣膜由称为心垫的前体结构发育而来，心垫是一种位于心管内侧的内皮衬里的心脏果冻。然后，来自不同来源的细胞侵入垫中，经历一系列复杂且知之甚少的重塑过程，并产生瓣膜。成纤维细胞生长因子 (FGF) 信号轴的破坏会损害流出道 (OFT) 的形态发生。然而，FGF 信号是否调节 OFT 瓣膜形成尚不清楚。
研究 OFT 瓣膜形成是如何受到调节的，以及异常细胞信号如何导致瓣膜缺陷。
通过使用小鼠遗传操作、细胞谱系追踪、心脏外植体培养和分子生物学方法，我们证明了 OFT 心肌中的 FGF 信号上调了 Bmp4 的表达，从而增强了神经嵴细胞 (NCC) 在垫中的平滑肌分化。FGF 信号还促进了 OFT 心肌细胞向垫的侵袭。破坏 FGF 信号会中断垫的重塑，导致 NCC 向平滑肌分化减少，心肌细胞侵袭减少，从而导致 OFT 瓣膜畸形。
研究结果表明，FGF-BMP 信号轴通过控制垫 NCC 的平滑肌分化来调节 OFT 瓣膜原基形成的新机制。
