Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche
Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche
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DOI：
10.1182/blood-2011-01-332890
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发表时间：
2011-08-11
期刊：
影响因子：
20.3
通讯作者：
Cammenga, Jorg
中科院分区：
文献类型：
--
作者：
Rehn, Matilda;Olsson, Andre;Cammenga, Jorg
缺氧正在成为造血干细胞（HSC）生态位的一个重要特征，但有助于静止、自我更新和生存的分子机制仍然难以捉摸。血管内皮生长因子 A (VEGFA) 是血管生成和造血的关键调节因子。其表达通常受到缺氧诱导因子 (HIF) 的调节，这些因子在低氧条件下功能性诱导，并通过与缺氧反应元件 (HRE) 结合来激活转录。 Vegfa 对于 HSC 的存活是不可或缺的，由细胞内在的自分泌机制介导。我们假设低氧的 HSC 微环境是维持或上调 HSC 中 Vegfa 表达所必需的，因此对于 HSC 的存活至关重要。我们在小鼠模型 Vegfa(delta/delta) 中测试了这一假设，其中 Vegfa 启动子中的 HRE 发生突变，阻止了 HIF 结合。来自 Vegfa(delta/delta) 小鼠的高度纯化的 HSC 中 Vegfa 表达降低，表明 HSC 存在于缺氧区域。缺氧调节的 Vegfa 表达的丧失会增加表型定义的造血干细胞和祖细胞的数量。然而，在竞争性移植试验中评估时，HSC 功能明显受损。我们的数据进一步证明 HSC 存在于缺氧微环境中，并证明缺氧微环境通过缺氧-VEGFA 轴影响 HSC 命运的新方式。 （血。2011；118(6):1534-1543）
Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or up-regulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(delta/delta), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(delta/delta) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-VEGFA axis. (Blood. 2011;118(6):1534-1543)