Targeted Vezf1-null mutation impairs vascular structure formation during embryonic stem cell differentiation.
Targeted Vezf1-null mutation impairs vascular structure formation during embryonic stem cell differentiation.
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DOI：
10.1161/atvbaha.109.200428
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Stuhlmann H
中科院分区：
文献类型：
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作者：
Zou Z;Ocaya PA;Sun H;Kuhnert F;Stuhlmann H
Vezf1是一种早期锌指转录因子，对正常血管发育和功能具有剂量依赖性。本研究通过体外胚胎样体分化模型和体内畸胎癌模型研究Vezf1突变体ES细胞，探讨Vezf1在内皮细胞分化和成熟过程中的作用。Vezf1−/−ES细胞衍生的胚状体未能形成组织良好的维管网络，并表现出明显的维管发芽缺陷。我们的研究结果表明，视黄醇通路是Vezf1功能的重要介质，Vezf1的缺失导致视黄醇/维生素A信号传导减少和细胞外基质形成异常。出乎意料的是，我们还发现了Vezf1−/−ES细胞沿造血细胞系体外分化过程中的缺陷。Vezf1−/−ES细胞衍生的畸胎癌能够自发分化为所有三种胚层的细胞类型。然而，这些肿瘤的组织学和免疫组织化学检查显示细胞增殖减少，分化延迟，细胞灶大，细胞外基质广泛沉积。胚状体和畸胎瘤来源于杂合的胚胎干细胞，表现出一种中间表型。综上所述，这些结果表明Vezf1通过调节细胞分化、增殖、ECM分布和沉积，参与了脉管系统的早期分化过程。
Vezf1 is an early zinc finger transcription factor that is essential for normal vascular development and functions in a dose-dependent manner. Here, we investigated the role of Vezf1 during processes of endothelial cell differentiation and maturation by studying mutant Vezf1 ES cells using the in vitro embryoid body differentiation model and the in vivo teratocarcinoma model. Vezf1−/− ES cell-derived embryoid bodies failed to form a well-organized vascular network and showed dramatic vascular sprouting defects. Our results indicate that the retinol pathway is an important mediator of Vezf1 function, and that loss of Vezf1 results in reduced retinol/Vitamin A signaling and aberrant extracellular matrix formation. Unexpectedly, we also uncovered defects during in vitro differentiation of Vezf1−/− ES cells along hematopoietic cell lineages. Vezf1−/− ES cell-derived teratocarcinomas were able to spontaneously differentiate into cell types of all three germ layers. However, histological and immunohistochemical examination of these tumors showed decreased cell proliferation, delayed differentiation, and large foci of cells with extensive deposition of extracellular matrix. Embryoid bodies and teratocarcinomas derived from heterozygous ES cells displayed an intermediate phenotype. Together, these results suggest that Vezf1 is involved in early differentiation processes of the vasculature by regulating cell differentiation, proliferation, and ECM distribution and deposition.