Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells
Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells
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DOI：
10.1182/blood-2012-05-432260
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发表时间：
2012-12-13
期刊：
影响因子：
20.3
通讯作者：
Sadek, Hesham A.
中科院分区：
文献类型：
--
作者：
Kocabas, Fatih;Zheng, Junke;Sadek, Hesham A.
Meis1在白血病中的作用已经得到了很好的证实，但它在造血干细胞(HSCs)中的作用仍不清楚。在此之前，我们发现HSCs利用糖酵解代谢来满足其能量需求。然而，HSC代谢的调节机制以及维持这种独特的代谢表型对HSC功能的重要性尚未确定。更重要的是，Meis1在HSCs中的主要功能仍不清楚。在这里，我们研究了Meis1基因缺失对HSC功能和代谢的影响。成年小鼠HSCs中可诱导的Meis1缺失导致HSC静止期丧失，移植后骨髓再生失败。虽然我们之前证明了Meis1在体外调节Hif-1α的转录，但在这里我们证明了Meis1的缺失导致Hif-1α和Hif-2α在HSCs中的下调。这导致了HSCs向线粒体代谢的转变，增加了活性氧的产生，并导致了HSC的凋亡。最后，我们证明了Meis1基因敲除对HSC的影响完全是通过活性氧介导的，清除剂N-乙酰半胱氨酸处理Meis1基因敲除小鼠恢复了HSC的静止并挽救了HSC的功能。这些结果揭示了一个重要的转录网络，它调节着HSCs的新陈代谢、氧化防御和维持。(血。2012年；120(25)：4963-4972)
The role of Meis1 in leukemia is well established, but its role in hematopoietic stem cells (HSCs) remains poorly understood. Previously, we showed that HSCs use glycolytic metabolism to meet their energy demands. However, the mechanism of regulation of HSC metabolism, and the importance of maintaining this distinct metabolic phenotype on HSC function has not been determined. More importantly, the primary function of Meis1 in HSCs remains unknown. Here, we examined the effect of loss of Meis1 on HSC function and metabolism. Inducible Meis1 deletion in adult mouse HSCs resulted in loss of HSC quiescence, and failure of bone marrow repopulation after transplantation. While we previously showed that Meis1 regulates Hif-1 alpha transcription in vitro, we demonstrate here that loss of Meis1 results in down-regulation of both Hif-1 alpha and Hif-2 alpha in HSCs. This resulted in a shift to mitochondrial metabolism, increased reactive oxygen species production, and apoptosis of HSCs. Finally, we demonstrate that the effect of Meis1 knockout on HSCs is entirely mediated through reactive oxygen species where treatment of the Meis1 knockout mice with the scavenger N-acetylcystein restored HSC quiescence and rescued HSC function. These results uncover an important transcriptional network that regulates metabolism, oxidant defense, and maintenance of HSCs. (Blood. 2012; 120(25): 4963-4972)