VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism
VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism
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DOI：
10.1038/nature00821
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发表时间：
2002-06-27
期刊：
影响因子：
64.8
通讯作者：
Ferrara, N
中科院分区：
文献类型：
--
作者：
Gerber, HP;Malik, AK;Ferrara, N
血管内皮生长因子 (VEGF) 是血管形成和造血的主要调节因子 (1,2)，但 VEGF 差异调节这些过程的机制尚不清楚。在这里，我们描述了 VEGF 控制造血干细胞 (HSC) 存活的调节环路。我们观察到小鼠体内 VEGF 基因被消除后，HSC 的存活率、集落形成率和体内再增殖率均降低。细胞内作用的 VEGF 受体 (VEGFR) 酪氨酸激酶小分子抑制剂可显着减少 HSC 集落形成，从而模拟 VEGF 基因的缺失。然而，通过施用在细胞外发挥作用的可溶性 VEGFR-1 来阻断 VEGF，仅产生很小的效果。这些发现支持 VEGF 依赖性内部自分泌环机制参与 HSC 存活（即，该机制对无法穿透细胞内区室的抑制剂具有抵抗力）。不仅对 VEGF 和 VEGFR-2 具有选择性的配体，而且 VEGFR-1 激动剂也能挽救 VEGF 缺陷型 HSC 的存活和增殖，揭示了造血过程中 VEGFR-1 信号传导的功能。
Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis(1,2), but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis.