Molecular events in MSC exosome mediated cytoprotection in cardiomyocytes
Molecular events in MSC exosome mediated cytoprotection in cardiomyocytes
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DOI：
10.1038/s41598-019-55694-7
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发表时间：
2019-12-17
影响因子：
4.6
通讯作者：
Mehta, Jawahar L.
中科院分区：
文献类型：
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作者：
Kore, Rajshekhar A.;Henson, Jeffrey C.;Mehta, Jawahar L.
心肌细胞暴露于缺氧和其他有害刺激后，会发生大量的代谢改变。在这里，我们证明，暴露于培养的大鼠心肌细胞脂多糖（LPS）导致上调（类似于1.5倍）的氧化低密度脂蛋白受体-1（LOX-1）。在LPS处理后12小时，细胞凋亡也显著增加，胱天蛋白酶-3水平显著升高（类似于1.3倍），并且在24小时LDH释放显著增加。有趣的是，LPS处理后LC-3表达有类似于1.4倍的上调，表明自噬的发展，这可能是对抗LPS诱导的细胞损伤的补偿反应。用LPS处理也减少了心肌细胞球体的大小和形态。为了限制LPS诱导的损伤，用来源于间充质基质I细胞（MSC）的外来体处理心肌细胞。我们注意到LOX-1表达的显著抑制，进而抑制细胞凋亡以及自噬反应并恢复球体形态。MSC外泌体的质谱分光光度分析揭示了富含蛋白质的货物，所述蛋白质参与负调节细胞死亡和凋亡同时促进细胞存活的途径。这是第一次报告，以我们的知识在MSC外泌体介导的细胞保护应激心肌细胞的初始分子事件。
A host of hormonal-metabolic alterations take place following exposure of cardiomyocytes to hypoxia and other noxious stimuli. Here, we demonstrate that exposure of cultured rat cardiomyocytes to lipopolysaccharide (LPS) resulted in upregulation (similar to 1.5 fold) of oxidized low-density lipoprotein receptor-1 (LOX-1). There was also a marked increase in apoptosis 12 hrs after LPS treatment with caspase-3 levels being significantly elevated (similar to 1.3 fold) and a significant increase in LDH release at 24 hrs. Interestingly, there was a similar to 1.4-fold upregulation of LC-3 expression post-LPS treatment indicating development of autophagy, which probably is a compensatory response to combat cellular injury induced by LPS. Treatment with LPS also reduced the size and morphology of cardiomyocyte spheroids. In an attempt to limit LPS-induced injury, cardiomyocytes were treated with exosomes derived from mesenchymal stroma I cells (MSCs). We noted a significant suppression of LOX-1 expression that in turn suppressed apoptosis as well as autophagic response and restored spheroid morphology. Mass spectrophotometric analysis of MSC exosomes revealed a cargo rich in proteins which are involved in pathways negatively modulating cell death and apoptosis while promoting cell survival. This is first report to our knowledge on the initial molecular events in MSC exosome mediated cytoprotection of stressed cardiomyocytes.