Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis
Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis
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DOI：
10.1242/jcs.052324
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发表时间：
2009-11-01
影响因子：
4
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Harada, Kaori;Yamazaki, Tomoko;Miyazono, Kohei
在淋巴管发育过程中，Prox1 在血管内皮细胞 (BEC) 分化为淋巴管内皮细胞 (LEC) 以及随后淋巴管的成熟和维持中发挥核心作用。然而，Prox1 引发这些功能的分子机制仍有待阐明。在这里，我们确定了在淋巴管成熟中发挥重要作用的 FoxC2 和血管生成素-2 (Ang2)，作为小鼠胚胎干细胞源性内皮细胞 (MESEC) 中 Prox1 的新靶标。此外，我们发现 MESEC 中 Prox1 显着诱导 HoxD8 的表达，这一发现在人脐静脉内皮细胞 (HUVEC) 和人真皮 LEC (HDLEC) 中得到证实。在小鼠胚胎中，LEC 中的 HoxD8 表达显着高于 BEC 中。在炎症淋巴管生成模型中，腺病毒转导的 HoxD8 增加了膈肌淋巴管的直径。我们还发现 HoxD8 诱导 HDLEC 和 HUVEC 中 Ang2 的表达。此外，我们发现HoxD8在HUVEC中诱导Prox1表达，并且HoxD8的敲低降低了HDLEC中的这种表达，表明LEC中Prox1的表达是由HoxD8维持的。这些发现表明 Prox1 和 HoxD8 的转录网络在淋巴管的成熟和维护中发挥重要作用。
During lymphatic development, Prox1 plays central roles in the differentiation of blood vascular endothelial cells (BECs) into lymphatic endothelial cells (LECs), and subsequently in the maturation and maintenance of lymphatic vessels. However, the molecular mechanisms by which Prox1 elicits these functions remain to be elucidated. Here, we identified FoxC2 and angiopoietin-2 (Ang2), which play important roles in the maturation of lymphatic vessels, as novel targets of Prox1 in mouse embryonic-stem-cell-derived endothelial cells (MESECs). Furthermore, we found that expression of HoxD8 was significantly induced by Prox1 in MESECs, a finding confirmed in human umbilical vein endothelial cells (HUVECs) and human dermal LECs (HDLECs). In mouse embryos, HoxD8 expression was significantly higher in LECs than in BECs. In a model of inflammatory lymphangiogenesis, diameters of lymphatic vessels of the diaphragm were increased by adenovirally transduced HoxD8. We also found that HoxD8 induces Ang2 expression in HDLECs and HUVECs. Moreover, we found that HoxD8 induces Prox1 expression in HUVECs and that knockdown of HoxD8 reduces this expression in HDLECs, suggesting that Prox1 expression in LECs is maintained by HoxD8. These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels.