EphB4 forward-signaling regulates cardiac progenitor development in mouse ES cells.
EphB4 forward-signaling regulates cardiac progenitor development in mouse ES cells.
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DOI：
10.1002/jcb.25000
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发表时间：
2015-03
影响因子：
4
通讯作者：
Wang, Zack Z.
中科院分区：
文献类型：
--
作者：
Chen, Kang;Bai, Hao;Liu, Yanfeng;Hoyle, Dixie L.;Shen, Wei-Feng;Wu, Li-Qun;Wang, Zack Z.
Eph受体（Eph）-肝配蛋白信号在器官发育和组织再生中发挥重要作用。 EphB4-ephrinB2 的双向信号传导调节心血管发育。为了评估 EphB4-ephrinB2 信号在心脏谱系发育中的作用，我们在胚胎干 (ES) 细胞中使用了两个 GFP 报告系统，其中 GFP 转基因分别在 Nkx2.5+ 心脏祖细胞和 α-MHC+ 心肌细胞中表达。我们发现，在 ES 细胞的心脏谱系分化过程中，EphB4 和 ephrinB2 在 Nkx2.5-GFP+ 心脏祖细胞中表达，但在 α-MHC-GFP+ 心肌细胞中不表达。 TNYL-RAW 肽是 EphB4 的拮抗剂，可阻断 EphB4 和 ephrinB2 的结合，从而损害 ES 细胞中心脏谱系的发育。在 ES 细胞分化过程中不同时间点抑制 EphB4-ephrinB2 信号传导表明，EphB4 和 ephrinB2 的相互作用是心脏谱系发育早期阶段所必需的。在 EphB4 缺失的 ES 细胞中强制表达人全长 EphB4 或胞内结构域截短的 EphB4，以研究 EphB4 前向信号在 ES 细胞中的作用。有趣的是，虽然全长EphB4能够恢复EphB4缺失ES细胞中心脏谱系的发育，但缺乏酪氨酸激酶胞内结构域和PDZ基序的截短EphB4却未能挽救心肌细胞发育的缺陷，这表明EphB4胞内结构域对于心肌细胞的发育至关重要。我们的研究提供了证据，证明受体激酶依赖性 EphB4 正向信号在心脏祖细胞的发育中起着至关重要的作用。 J.细胞。生物化学。 116: 467–475, 2015。© 2014 作者。 《细胞生物化学杂志》由 Wiley periodicals, Inc. 出版
Eph receptor (Eph)‐ephrin signaling plays an important role in organ development and tissue regeneration. Bidirectional signaling of EphB4–ephrinB2 regulates cardiovascular development. To assess the role of EphB4–ephrinB2 signaling in cardiac lineage development, we utilized two GFP reporter systems in embryonic stem (ES) cells, in which the GFP transgenes were expressed in Nkx2.5+ cardiac progenitor cells and in α‐MHC+ cardiomyocytes, respectively. We found that both EphB4 and ephrinB2 were expressed in Nkx2.5‐GFP+ cardiac progenitor cells, but not in α‐MHC‐GFP+ cardiomyocytes during cardiac lineage differentiation of ES cells. An antagonist of EphB4, TNYL‐RAW peptides, that block the binding of EphB4 and ephrinB2, impaired cardiac lineage development in ES cells. Inhibition of EphB4–ephrinB2 signaling at different time points during ES cell differentiation demonstrated that the interaction of EphB4 and ephrinB2 was required for the early stage of cardiac lineage development. Forced expression of human full‐length EphB4 or intracellular domain‐truncated EphB4 in EphB4‐null ES cells was established to investigate the role of EphB4‐forward signaling in ES cells. Interestingly, while full‐length EphB4 was able to restore the cardiac lineage development in EphB4‐null ES cells, the truncated EphB4 that lacks the intracellular domain of tyrosine kinase and PDZ motif failed to rescue the defect of cardiomyocyte development, suggesting that EphB4 intracellular domain is essential for the development of cardiomyocytes. Our study provides evidence that receptor‐kinase‐dependent EphB4‐forward signaling plays a crucial role in the development of cardiac progenitor cells. J. Cell. Biochem. 116: 467–475, 2015. © 2014 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.
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