Haematopoietic Stem Cell Laboratory, London Research Institute, Cancer Research UK, WC2A 3LY, London, UK; INSERM U 1035, Bordeaux, F-33076 France; Université Bordeaux Segalen, Bordeaux, F-33076 France.
Cell Stem Cell. 2013 Nov 7;13(5):549-63. doi: 10.1016/j.stem.2013.08.011. Epub 2013 Oct 3.
Hematopoietic stem and progenitor cells (HSPCs) are exposed to low levels of oxygen in the bone marrow niche, and hypoxia-inducible factors (HIFs) are the main regulators of cellular responses to oxygen variation. Recent studies using conditional knockout mouse models have unveiled a major role for HIF-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear. Here, we show that knockdown of HIF-2α, and to a much lesser extent HIF-1α, impedes the long-term repopulating ability of human CD34(+) umbilical cord blood cells. HIF-2α-deficient HSPCs display increased production of reactive oxygen species (ROS), which subsequently stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells.
造血干细胞和祖细胞（HSPCs）在骨髓龛中处于低氧环境，缺氧诱导因子（HIFs）是细胞对氧变化反应的主要调节因子。最近使用条件性敲除小鼠模型的研究揭示了 HIF-1α 在维持小鼠 HSPCs 中的主要作用；然而，HIF-2α 的作用尚不清楚。在这里，我们表明 HIF-2α 的敲低，以及在较小程度上 HIF-1α 的敲低，会阻碍人脐血 CD34+细胞的长期重编程能力。HIF-2α 缺陷的 HSPCs 显示出活性氧（ROS）的产生增加，这随后通过未折叠蛋白反应（UPR）途径的激活刺激内质网（ER）应激并引发细胞凋亡。HIF-2α 的失调也显著降低了人急性髓系白血病（AML）细胞的植入能力。总体而言，我们的数据表明 HIF-2α 在维持人类 HSPCs 和原发性 AML 细胞的存活中起着关键作用。
