Messina-Graham Steven, Broxmeyer Hal
Department of Microbiology and Immunology, Indiana University School of Medicine, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, USA.
Blood Cells Mol Dis. 2016 May;58:13-8. doi: 10.1016/j.bcmd.2016.01.008. Epub 2016 Jan 28.
SDF-1/CXCL12 is a potent chemokine required for the homing and engraftment of hematopoietic stem and progenitor cells. Previous data from our group has shown that in an SDF-1/CXCL12 transgenic mouse model, lineage(-) Sca-1(+) c-Kit(+) (LSK) bone marrow cells have reduced mitochondrial membrane potential versus wild-type. These results suggested that SDF-1/CXCL12 may function to keep mitochondrial respiration low in immature blood cells in the bone marrow. Low mitochondrial metabolism helps to maintain low levels of reactive oxygen species (ROS), which can influence differentiation. To test whether SDF-1/CXCL12 regulates mitochondrial metabolism, we employed the human leukemia cell line HL-60, that expresses high levels of the SDF-1/CXCL12 receptor, CXCR4, as a model of hematopoietic progenitor cells in vitro. We treated HL-60 cells with SDF-1/CXCL12 for 2 and 24h. Oxygen consumption rates (OCR), mitochondrial-associated ATP production, mitochondrial mass, and mitochondrial membrane potential of HL-60 cells were significantly reduced at 2h and increased at 24h as compared to untreated control cells. These biphasic effects of SDF-1/CXCL12 were reproduced with lineage negative primary mouse bone marrow cells, suggesting a novel function of SDF-1/CXCL12 in modulating mitochondrial respiration by regulating mitochondrial oxidative phosphorylation, ATP production and mitochondrial content.
基质细胞衍生因子-1/趋化因子配体12（SDF-1/CXCL12）是造血干细胞和祖细胞归巢及植入所必需的一种强效趋化因子。我们团队之前的数据表明，在SDF-1/CXCL12转基因小鼠模型中，谱系（-）干细胞抗原-1（Sca-1）阳性c-Kit阳性（LSK）骨髓细胞与野生型相比，线粒体膜电位降低。这些结果提示，SDF-1/CXCL12可能在维持骨髓中未成熟血细胞的线粒体低呼吸水平方面发挥作用。低线粒体代谢有助于维持低水平的活性氧（ROS），而ROS会影响细胞分化。为了测试SDF-1/CXCL12是否调节线粒体代谢，我们使用了人白血病细胞系HL-60，该细胞系表达高水平的SDF-1/CXCL12受体CXCR4，作为体外造血祖细胞的模型。我们用SDF-1/CXCL12处理HL-60细胞2小时和24小时。与未处理的对照细胞相比，HL-60细胞的氧消耗率（OCR）、线粒体相关的ATP产生、线粒体质量和线粒体膜电位在2小时时显著降低，在24小时时升高。SDF-1/CXCL12的这些双相效应在谱系阴性的原代小鼠骨髓细胞中也得到了重现，这表明SDF-1/CXCL12在通过调节线粒体氧化磷酸化、ATP产生和线粒体含量来调节线粒体呼吸方面具有新功能。
