MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells
MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells
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MDH1介导的苹果酸-天冬氨酸NADH穿梭维持胎儿肝脏造血干细胞的活性水平
DOI：
10.1182/blood.2019003940
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发表时间：
2020-07-30
期刊：
影响因子：
20.3
通讯作者：
Zheng, Junke
中科院分区：
文献类型：
--
作者：
Gu, Hao;Chen, Chiqi;Zheng, Junke
造血干细胞（HSCs）在不同发育阶段的能量代谢和干细胞性之间的联系仍然很大程度上未知。我们建立了一个转基因小鼠品系，并根据SoNar荧光的比例证明了有3个不同的胎肝造血细胞群。SoNar低表达细胞的线粒体反应增强，但糖酵解水平与SoNar高表达细胞相似。有趣的是，10%的SoNar-低细胞富集了65%的总免疫表型胎肝HSC（FL-HSC），并且含有比其SoNar-高对应物多约5倍的功能性HSC。SoNar能敏感地监测体外和体内HSC能量代谢的动态变化。在机制上，STAT 3反式激活MDH 1以维持苹果酸-天冬氨酸NADH穿梭活性和HSC自我更新和分化。我们揭示了FL-HSC的一个意想不到的代谢程序，并为HSC或其他类型干细胞的代谢研究提供了一个强大的遗传工具。
The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and dem-onstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial res-piration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for meta-bolic studies of HSCs or other types of stem cells.