Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival
Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival
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DOI：
10.1523/jneurosci.0526-06.2006
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发表时间：
2006-06-21
影响因子：
5.3
通讯作者：
van der Kooy, Derek
中科院分区：
文献类型：
--
作者：
Wada, Tamaki;Haigh, Jody J.;van der Kooy, Derek
神经干细胞（NSC）有两种类型。原始 NSC [依赖于白血病抑制因子 (LIF)，但不依赖于外源成纤维细胞生长因子 (FGF) 2] 在体外可源自小鼠胚胎干 (ES) 细胞，在体内可源自胚胎第 5.5 天 (E5.5) 至 E7.5 外胚层和 E7.5-E8.5 神经外胚层。确定性 NSC（不依赖于 LIF，但依赖于 FGF2）首先出现在 E8.5 神经板中，并持续存在于整个生命周期。原始 NSC 产生最终的 NSC。利用功能丧失和获得来研究血管内皮生长因子 (VEGF)-A 及其受体 Flk1 在 NSC 中的作用。 Flk1敲除小鼠胚胎来源和ES细胞来源的原始NSCs数量增加，因为原始NSCs的存活率提高。相比之下，神经前体特异性、Flk1 条件性敲除小鼠来源的、最终 NSC 数量减少，因为最终 NSC 的细胞死亡增加。在缺乏另一种 VEGF 受体 Flt1 的细胞中没有观察到这些效应。此外，原始NSC的VEGF-A刺激的细胞死亡和最终NSC的VEGF-A刺激的细胞存活被Flk1/Fc可溶性受体和VEGF-A功能阻断抗体阻断。这些 VEGF-A 表型也可以通过抑制下游效应核因子 kappa B (NF-kappa B) 来阻断。因此，VEGF-A 刺激诱导的原始 NSC 的细胞死亡和最终 NSC 的细胞存活都是由双功能 NF-κ B 效应介导的。总之，VEGF-A 通过 Flk1 发挥作用，特别介导对 NSC 的生存（而不是增殖或命运改变）影响。
There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF) dependent but exogenous fibroblast growth factor (FGF) 2 independent] can be derived from mouse embryonic stem (ES) cells in vitro and from embryonic day 5.5 (E5.5) to E7.5 epiblast and E7.5-E8.5 neuroectoderm in vivo. Definitive NSCs (LIF independent but FGF2 dependent) first appear in the E8.5 neural plate and persist throughout life. Primitive NSCs give rise to definitive NSCs. Loss and gain of functions were used to study the role of vascular endothelial growth factor (VEGF)-A and its receptor, Flk1, in NSCs. The numbers of Flk1 knock-out mice embryo-derived and ES cell-derived primitive NSCs were increased because of the enhanced survival of primitive NSCs. In contrast, neural precursor-specific, Flk1 conditional knock-out mice-derived, definitive NSCs numbers were decreased because of the enhanced cell death of definitive NSCs. These effects were not observed in cells lacking Flt1, another VEGF receptor. In addition, the cell death stimulated by VEGF-A of primitive NSC and the cell survival stimulated by VEGF-A of definitive NSC were blocked by Flk1/Fc-soluble receptors and VEGF-A function-blocking antibodies. These VEGF-A phenotypes also were blocked by inhibition of the downstream effector nuclear factor kappa B (NF-kappa B). Thus, both the cell death of primitive NSC and the cell survival of definitive NSC induced by VEGF-A stimulation are mediated by bifunctional NF-kappa B effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.