Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo.
Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo.
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DOI：
10.1161/circresaha.108.177238
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发表时间：
2008-10-24
影响因子：
20.1
通讯作者：
Lincoln J
中科院分区：
文献类型：
--
作者：
Levay AK;Peacock JD;Lu Y;Koch M;Hinton RB Jr;Kadler KE;Lincoln J
心脏瓣膜结构源自间充质前体细胞，由分化的细胞类型和排列以促进瓣膜功能的细胞外基质组成。巩膜轴（scx）是肌腱细胞分化和基质组织所需的转录因子。该研究使用scx-GFP报告小鼠鉴定了在胚胎第15.5天至出生后阶段重塑心脏瓣膜结构中的高水平scx表达，并使用scx无效的小鼠确定了体内功能。Scx−/−小鼠从胚胎第17.5天开始显示出显着增厚的心脏瓣膜结构，突变小鼠的瓣膜显示出瓣膜前体细胞分化和基质组织的改变。这是由肌腱相关的胶原蛋白XIV型的表达减少，软骨相关基因（包括sox 9）的表达增加，以及间充质细胞标志物（包括msx 1和snai 1）的持续表达所指示的。此外，超微结构分析显示瓣叶内细胞外基质和胶原纤维组织混乱。在幼年scx−/−小鼠中观察到人类心脏瓣膜疾病特征性的瓣膜结构增厚和基质重塑基因表达增加。此外，在房室交界处的环形结构中观察到过度的胶原沉积。总的来说，我们的研究已经确定了在瓣膜形成过程中scx的体内需求，并证明了其在重塑瓣膜结构的细胞谱系分化和基质分布中的作用。
Heart valve structures, derived from mesenchyme precursor cells, are composed of differentiated cell types and extracellular matrix arranged to facilitate valve function. Scleraxis (scx) is a transcription factor required for tendon cell differentiation and matrix organization. This study identified high levels of scx expression in remodeling heart valve structures at embryonic day 15.5 through postnatal stages using scx-GFP reporter mice and determined the in vivo function using mice null for scx. Scx−/− mice display significantly thickened heart valve structures from embryonic day 17.5, and valves from mutant mice show alterations in valve precursor cell differentiation and matrix organization. This is indicated by decreased expression of the tendon-related collagen type XIV, increased expression of cartilage-associated genes including sox9, as well as persistent expression of mesenchyme cell markers including msx1 and snai1. In addition, ultrastructure analysis reveals disarray of extracellular matrix and collagen fiber organization within the valve leaflet. Thickened valve structures and increased expression of matrix remodeling genes characteristic of human heart valve disease are observed in juvenile scx−/− mice. In addition, excessive collagen deposition in annular structures within the atrioventricular junction is observed. Collectively, our studies have identified an in vivo requirement for scx during valvulogenesis and demonstrate its role in cell lineage differentiation and matrix distribution in remodeling valve structures.