Hypoxic metabolism in human hematopoietic stem cells.
Hypoxic metabolism in human hematopoietic stem cells.
复制标题
人类造血干细胞的缺氧代谢
DOI：
10.1186/s13578-015-0020-3
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发表时间：
2015
影响因子：
7.5
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Kocabas F;Xie L;Xie J;Yu Z;DeBerardinis RJ;Kimura W;Thet S;Elshamy AF;Abouellail H;Muralidhar S;Liu X;Chen C;Sadek HA;Zhang CC;Zheng J
背景成体造血干细胞（hematopoietic stem cells，HSCs）维持在骨髓内骨内膜区的微环境中，称为微环境。这种低氧张力的干细胞生态位需要HSC采用独特的代谢谱。我们最近证明，小鼠长期造血干细胞（LT-HSC）利用糖酵解而不是线粒体氧化磷酸化作为其主要能量来源。然而，人类造血祖细胞和干细胞（HPSCs）的代谢表型仍然unknown.ResultsWe表明，HPSCs有一个类似的代谢表型，所示的糖酵解的高速率，和低速率的耗氧量。基于其代谢足迹的人动员的外周血细胞的分级显示，具有低线粒体电位的细胞高度富集HPSC。值得注意的是，与高MP细胞相比，低MP细胞具有更好的再增殖能力。此外，与它们的鼠对应物类似，我们表明Hif-1α在人HPSC中上调，其中它由Meis 1转录调节。最后，我们发现Meis 1及其辅因子Pbx 1和HoxA 9在HIF-1α的转录激活中起着重要的作用。结论这些发现突出了人类HPSCs独特的代谢特性和调控其代谢表型的转录网络。
BackgroundAdult hematopoietic stem cells (HSCs) are maintained in a microenvironment, known as niche in the endosteal regions of the bone marrow. This stem cell niche with low oxygen tension requires HSCs to adopt a unique metabolic profile. We have recently demonstrated that mouse long-term hematopoietic stem cells (LT-HSCs) utilize glycolysis instead of mitochondrial oxidative phosphorylation as their main energy source. However, the metabolic phenotype of human hematopoietic progenitor and stem cells (HPSCs) remains unknown.ResultsWe show that HPSCs have a similar metabolic phenotype, as shown by high rates of glycolysis, and low rates of oxygen consumption. Fractionation of human mobilized peripheral blood cells based on their metabolic footprint shows that cells with a low mitochondrial potential are highly enriched for HPSCs. Remarkably, low MP cells had much better repopulation ability as compared to high MP cells. Moreover, similar to their murine counterparts, we show that Hif-1α is upregulated in human HPSCs, where it is transcriptionally regulated by Meis1. Finally, we show that Meis1 and its cofactors Pbx1 and HoxA9 play an important role in transcriptional activation of Hif-1α in a cooperative manner.ConclusionsThese findings highlight the unique metabolic properties of human HPSCs and the transcriptional network that regulates their metabolic phenotype.