Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair.
Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair.
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DOI：
10.1002/stem.1935
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发表时间：
2015-04
期刊：
影响因子：
5.2
通讯作者：
Young, Pampee P.
中科院分区：
文献类型：
--
作者：
Saraswati, Sarika;Guo, Yan;Atkinson, James;Young, Pampee P.
间充质干细胞在伤口微环境中遭遇长时间缺氧，但对其对这种长时间缺氧环境的适应性知之甚少。在这项研究中，我们评估了MSCs在长期缺氧（1% O2）和常氧（20% O2）培养下的细胞和分子反应。长时间缺氧诱导MSCs向厌氧糖酵解转录组转换，并显著增加单羧酸转运体-4 （MCT4）的转录和蛋白质水平。为了阐明MCT4上调对MSC生物学的影响，我们在长时间缺氧培养后生成了MCT4稳定过表达的MSCs (MCT4-MSCs)，其水平与野生型（WT） MSCs相似。与MCT4-MSCs通过外排乳酸维持细胞内pH值的作用一致，MCT4-MSCs显示出细胞内乳酸减少。为了探讨MCT4上调在骨髓间充质干细胞治疗中的体内意义，我们在心肌梗死后给小鼠肌内注射对照(GFP)-MSCs、MCT4-MSCs或MCT4表达稳定沉默的MSCs （KDMCT4-MSCs）。MCT4过表达使心脏重塑和心功能恶化，而MCT4沉默可显著改善心功能。过表达mct4的间充质干细胞分泌组诱导活性氧介导的心肌细胞凋亡，但不诱导成纤维细胞凋亡；单独乳酸重现了MCT4-MSC分泌组的作用。我们的研究结果表明，mct4过表达的MSCs挤出的乳酸优先诱导心肌细胞的细胞死亡，而不是成纤维细胞，最终导致心功能下降和疤痕大小增加。更好地了解干细胞对长时间缺氧应激的反应以及由此产生的干细胞-肌细胞/成纤维细胞串导对于优化基于msc的心脏再生治疗是必要的。
MSCs encounter extended hypoxia in the wound microenvironment yet little is known about their adaptability to this prolonged hypoxic milieu. In this study, we evaluated the cellular and molecular response of MSCs in extended hypoxia (1% O2) vs. normoxia (20% O2) culture. Prolonged hypoxia induced a switch towards anaerobic glycolysis transcriptome and a dramatic increase in the transcript and protein levels of monocarboxylate transporter-4 (MCT4) in MSCs. To clarify the impact of MCT4 upregulation on MSC biology, we generated MSCs which stably overexpressed MCT4 (MCT4-MSCs) at levels similar to wildtype (WT) MSCs following prolonged hypoxic culture. Consistent with its role to efflux lactate to maintain intracellular pH, MCT4-MSCs demonstrated reduced intracellular lactate. To explore the in vivo significance of MCT4 upregulation in MSC therapy, mice were injected intramuscularly following MI with control (GFP)-MSCs, MCT4-MSCs or MSCs in which MCT4 expression was stably silenced (KDMCT4-MSCs). Overexpression of MCT4 worsened cardiac remodeling and cardiac function whereas silencing of MCT4 significantly improved cardiac function. MCT4-overexpressing MSC secretome induced reactive oxygen species-mediated cardiomyocyte but not fibroblast apoptosis in vitro and in vivo; lactate alone recapitulated the effects of the MCT4-MSC secretome. Our findings suggest that lactate extruded by MCT4-overexpressing MSCs preferentially induced cell death in cardiomyocytes but not in fibroblasts, leading ultimately to a decline in cardiac function and increased scar size. A better understanding of stem cells response to prolonged hypoxic stress and the resultant stem cell-myocyte/fibroblast cross-talk is necessary to optimize MSC-based therapy for cardiac regeneration.
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