MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
Hum Mol Genet. 2013 Dec 20;22(25):5083-95. doi: 10.1093/hmg/ddt358. Epub 2013 Jul 29.
The embryonic epicardium is an important source of cardiovascular precursor cells and paracrine factors that are required for adequate heart formation. Signaling pathways regulated by WT1 that promote heart development have started to be described; however, there is little information on signaling pathways regulated by WT1 that could act in a negative manner. Transcriptome analysis of Wt1KO epicardial cells reveals an unexpected role for WT1 in repressing the expression of interferon-regulated genes that could be involved in a negative regulation of heart morphogenesis. Here, we showed that WT1 is required to repress the expression of the chemokines Ccl5 and Cxcl10 in epicardial cells. We observed an inverse correlation of Wt1 and the expression of Cxcl10 and Ccl5 during epicardium development. Chemokine receptor analyses of hearts from Wt1(gfp/+) mice demonstrate the differential expression of their chemokine receptors in GFP(+) epicardial enriched cells and GFP(-) cells. Functional assays demonstrate that CXCL10 and CCL5 inhibit epicardial cells migration and the proliferation of cardiomyocytes respectively. WT1 regulates the expression levels of Cxcl10 and Ccl5 in epicardial cells directly and indirectly through increasing the levels of IRF7. As epicardial cell reactivation after a myocardial damage is linked with WT1 expression, the present work has potential implications in adult heart repair.
胚胎心外膜是心血管前体细胞和旁分泌因子的重要来源，这些细胞和因子是心脏正常形成所必需的。WT1 调节的信号通路促进心脏发育的机制已开始被描述；然而，WT1 调节的负向信号通路的信息却很少。对 Wt1KO 心外膜细胞的转录组分析揭示了 WT1 在抑制干扰素调节基因表达方面的意外作用，这些基因可能参与了心脏形态发生的负向调控。在这里，我们表明 WT1 抑制心外膜细胞中趋化因子 Ccl5 和 Cxcl10 的表达是必需的。我们观察到在心脏发育过程中心外膜 Wt1 的表达与 Cxcl10 和 Ccl5 的表达呈负相关。Wt1(gfp/+) 小鼠心脏的趋化因子受体分析表明，它们的趋化因子受体在 GFP(+)心外膜富集细胞和 GFP(-)细胞中存在差异表达。功能分析表明，CXCL10 和 CCL5 分别抑制心外膜细胞的迁移和心肌细胞的增殖。WT1 通过增加 IRF7 的水平，直接和间接调节心外膜细胞中 Cxcl10 和 Ccl5 的表达水平。由于心肌损伤后心外膜细胞的再激活与 WT1 的表达有关，本工作在心外膜细胞再激活与 WT1 的表达有关，本工作在成人心脏修复方面具有潜在的意义。
