Thrombopoietin (TPO) regulates HIF-la levels through generation of mitochondrial reactive oxygen species

缺氧诱导因子（Hypoxia inducible factor， HIF）-1是调节细胞对缺氧适应的主要转录调控因子。此外，HIF-1对造血干细胞（hsc）的发育也至关重要。在先前的研究中，我们发现血小板生成素（TPO）是一种重要的、非冗余的细胞因子，用于维持和扩增HSC，通过增强HIF-1 α在常压条件下的稳定性，诱导原始造血细胞中HIF-1 α的表达。然而，这些作用的分子机制尚不完全清楚。最近，有报道称线粒体活性氧（ROS）在缺氧诱导的HIF-1 α稳定中起着至关重要的作用。因此，我们推测ROS也可能参与tpo诱导的HIF-1 α表达。在UT-7/TPO细胞和原代未成熟小鼠骨髓细胞中，ROS清除剂和线粒体电子传递抑制剂完全阻断TPO诱导的HIF-1 α。这些结果表明，TPO诱导HIF-1 a表达的方式与缺氧非常相似，并有助于解释该激素对HSC发育至关重要的基因的有利作用。

Hypoxia inducible factor (HIF)-1 is a master transcriptional regulator mediating the cellular adaptation to hypoxia. In addition, HIF-1 is also vital for the development of hematopoietic stem cells (HSCs). In a previous study we found that thrombopoietin (TPO), an important and non-redundant cytokine for HSC maintenance and expansion, induces HIF-1 α expression in primitive hematopoietic cells by enhancing the stability of HIF-1 α under normoxic conditions. However, the molecular mechanism of these effects are not yet fully understood. Recently, it was reported that mitochondrial reactive oxygen species (ROS) play a crucial role in hypoxia-induced stabilization of HIF-1 α. Thus, we speculated that ROS might also be involved in TPO-induced HIF-1 α expression. Both ROS scavengers and inhibitors of mitochondrial electron transport completely blocked HIF-1 α induction by TPO in UT-7/TPO cells and in primary immature mouse bone marrow cells. These results indicate that TPO induces HIF-1 a expression in a manner very similar to that of hypoxia, and helps to explain the favorable effects of the hormone on genes vital for HSC development.