Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium.
Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium.
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DOI：
10.1002/stem.2856
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Lo EH
中科院分区：
文献类型：
--
作者：
Hayakawa K;Chan SJ;Mandeville ET;Park JH;Bruzzese M;Montaner J;Arai K;Rosell A;Lo EH
内皮祖细胞（EPCs）作为一种潜在的治疗中风和中枢神经系统损伤的细胞疗法一直受到关注。然而，它们的基本机制仍有待充分确定。最近的实验研究表明，线粒体可能被释放并在细胞间转移。在这项概念验证研究中，我们询问EPCs的有益作用是否也可能部分涉及线粒体现象。首先，收集epc衍生的条件培养基，离心后分为上清和颗粒馏分。电镜、免疫印迹和流式细胞术显示EPCs能够释放线粒体。ATP和耗氧量分析表明，这些细胞外线粒体可能仍然具有功能活力。共聚焦显微镜证实，epc来源的细胞外线粒体可以并入正常的脑内皮细胞。脑内皮细胞中添加EPC颗粒可促进血管生成，降低脑内皮细胞的跨细胞通透性。接下来，我们询问内皮细胞来源的线粒体是否可能具有保护作用。正如预期的那样，氧-葡萄糖剥夺增加了细胞内皮通透性。在受损的脑内皮中添加内皮细胞来源的线粒体颗粒可增加线粒体蛋白TOM40、mtDNA拷贝数和细胞内ATP的水平。除了这些线粒体转移的间接标记外，缺氧-葡萄糖剥夺后内皮紧密性也得到恢复。综上所述，这些发现表明EPCs可能部分通过细胞外线粒体转移支持脑内皮细胞能量、屏障完整性和血管生成功能。氧-葡萄糖剥夺后，内皮祖细胞（EPC）来源的线粒体颗粒到达受损的脑内皮，随着OGD后内皮松紧性的恢复，线粒体蛋白TOM40水平、mtDNA拷贝数和细胞内ATP水平升高。这些发现表明，EPCs可能部分通过细胞外线粒体转移支持脑内皮细胞能量、屏障完整性和血管生成功能。
Endothelial progenitor cells (EPCs) have been pursued as a potential cellular therapy for stroke and central nervous system injury. However, their underlying mechanisms remain to be fully defined. Recent experimental studies suggest that mitochondria may be released and transferred between cells. In this proof-of-concept study, we asked whether beneficial effects of EPCs may partly involve a mitochondrial phenomenon as well. First, EPC-derived conditioned medium was collected and divided into supernatant and particle fractions after centrifugation. Electron microscopy, western blots and flow cytometry showed that EPCs were able to release mitochondria. ATP and oxygen consumption assays suggested that these extracellular mitochondria may still be functionally viable. Confocal microscopy confirmed that EPC-derived extracellular mitochondria can be incorporated into normal brain endothelial cells. Adding EPC particles to brain endothelial cells promoted angiogenesis and decreased trans-cellular permeability of brain endothelial cells. Next, we asked whether EPC-derived mitochondria may be protective. As expected, oxygen-glucose deprivation increased trans-cellular endothelial permeability. Adding EPC-derived mitochondria particles to the damaged brain endothelium increased levels of mitochondrial protein TOM40, mtDNA copy number, and intracellular ATP. Along with these indirect markers of mitochondrial transfer, endothelial tightness was also restored after oxygen-glucose deprivation. Taken together, these findings suggest that EPCs may support brain endothelial energetics, barrier integrity and angiogenic function partly through extracellular mitochondrial transfer. Endothelial progenitor cell (EPC)-derived mitochondria particles to damaged brain endothelium after oxygen-glucose deprivation increased levels of mitochondrial protein TOM40, mtDNA copy number, and intracellular ATP along with restoring endothelial tightness after OGD. These findings suggest that EPCs may support brain endothelial energetics, barrier integrity and angiogenic function partly through extracellular mitochondrial transfer.
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