Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells
Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells
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DOI：
10.4161/cc.4.12.2197
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发表时间：
2005-12-01
期刊：
影响因子：
4.3
通讯作者：
Kaushansky, K
中科院分区：
文献类型：
--
作者：
Kirito, K;Kaushansky, K
血小板生成素(TPO)是一种关键的、非冗余的造血细胞因子，支持造血干/祖细胞的存活、自我更新活性和增殖，支持巨核细胞的生长和分化，支持其后代--血小板的功能激活。TPO通过调节几种转录因子的丰度或亚细胞定位来发挥这些作用，包括同源结构域蛋白HOXB4和HOXA9。除了这些作用外，TPO还有助于在支持造血干细胞(HSC)功能的骨髓微环境中协调细胞因子网络。在最近的研究中，我们发现TPO刺激血管内皮细胞生长因子(VEGF)的产生，这是另一种对HSC生理至关重要的细胞因子，促进HSC存活和扩增为承诺的造血祖细胞。与细胞因子的其他作用一样，TPO对VEGF表达的影响是通过稳定和激活负责VEGF表达的主要转录因子-氧张力反应低氧诱导因子-1(HIF-1)来实现的。再加上骨髓微环境是低氧的，低氧模拟了HSC的再填充活动，我们的观察表明，TPO模拟了低氧，并控制了HSC循环所需的重要基因，包括血管内皮生长因子，增加了我们对激素如何促进HSC功能的理解。
Thrombopoietin (TPO) is a pivotal and nonredundant hematopoietic cytokine, supporting the survival, self-renewal activity and proliferation of hematopoietic stem and progenitor cells, the growth and differentiation of megakaryocytes, and the functional activation of their progeny, blood platelets. TPO exerts these effects through regulating the abundance or subcellular localization of several transcription factors, including the homeodomain proteins HOXB4 and HOXA9. In addition to these effects, TPO helps orchestrate a cytokine-network in the bone marrow microenvironment that supports hematopoietic stem cell (HSC) function. In recent studies we have shown that TPO stimulates production of vascular endothelial cell growth factor ( VEGF), another cytokine vital for HSC physiology, promoting their survival and expansion into committed hematopoietic progenitors. Like several other effects of the cytokine, the effect of TPO on VEGF expression is mediated by stabilization and activation of the primary transcription factor responsible for VEGF expression, the oxygen tension responsive hypoxia inducible factor-1 (HIF-1). Together with the observation that bone marrow microenvironment is hypoxic and hypoxia simulates the repopulating activity of HSCs, our observations suggest that TPO mimics hypoxia and controls important genes required for HSC cycling, including VEGF, adding to our understanding of how the hormone contributes to HSC function.