Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2
Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2
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DOI：
10.1073/pnas.94.10.5141
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
LeDouarin, NM
中科院分区：
文献类型：
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作者：
Eichmann, A;Corbel, C;LeDouarin, NM
内皮细胞和造血细胞有一个共同的前体，称为成血管细胞，自本世纪初以来就被假设存在。最近，通过基因靶向删除内皮特异性血管内皮生长因子受体2 (VEGFR2)，表明在纯合子null mite中内皮细胞和造血细胞都不存在。这一观察结果表明，VEGFR2可以在成血管细胞中表达，并且对于其在两个谱系中的进一步分化至关重要。然而，不能排除造血功能衰竭是由于缺乏内皮细胞微环境而导致的次要效应的假设。为了区分这两种假设，我们制作了一种针对禽类VEGFR2细胞外结构域的单抗，并从鸡胚原肠胚期的中胚层分离出VEGFR2+细胞。我们发现，在克隆培养中，VEGPR2+细胞可以产生造血细胞集落或内皮细胞集落。发育决定似乎是由两种不同的VEGFR2配体结合调节的，因此，内皮分化需要VEGF，而造血分化发生在缺乏VEGF的情况下，并被可溶性的VEGFR2显著减少，这表明这一过程可能是由第二种尚未确定的VEGFR2配体介导的。这些观察结果强烈表明，在缺乏VEGFR2基因产物的情况下，造血细胞和血管内皮细胞的前体细胞都不能存活。因此，这些细胞可能是VEGFR2无效突变的初始目标。
The existence of a common precursor for endothelial and hemopoietic cells, termed the hemangioblast, has been postulated since the beginning of the century, Recently, deletion of the endothelial-specific vascular endo thelial growth factor receptor 2 (VEGFR2) by gene targeting has shown that both endothelial and hemopoietic cells are absent in homozygous null mite, This observation suggested that VEGFR2 could be expressed by the hemangioblast and essential for its further differentiation along both lineages, However, it was not possible to exclude the hypothesis that hemopoietic failure was a secondary effect resulting from the absence of an endothelial cell microenvironment. To distinguish between these two hypotheses, we have produced a mAb directed against the extracellular domain of avian VEGFR2 and isolated VEGFR2+ cells from the mesoderm of chicken embryos at the gastrulation stage, We have found that in clonal cultures, a VEGPR2+ cell gives rise to either a hemopoietic or an endothelial cell colony. The developmental decision appears to be regulated by the binding of two different VEGFR2 ligands, Thus, endothelial differentiation requires VEGF, whereas hemopoietic differentiation occurs in the absence of VEGF and is significantly reduced by soluble VEGFR2, showing that this process could be mediated by a second, yet unidentified, VEGFR2 ligand, These observations thus suggest strongly that in the absence of the VEGFR2 gene product, the precursors of both hemopoietic and vascular endothelial lineages cannot survive. These cells therefore might be the initial targets of the VEGFR2 null mutation.