Physiological levels of reactive oxygen species are required to maintain genomic stability in stem cells.
Physiological levels of reactive oxygen species are required to maintain genomic stability in stem cells.
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DOI：
10.1002/stem.438
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发表时间：
2010-07
期刊：
影响因子：
5.2
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
--
作者：
Li, Tao-Sheng;Marban, Eduardo
干细胞细胞遗传学异常构成了再生疗法的障碍。我们研究了活性氧（ROS）影响心脏和胚胎干细胞基因组稳定性的可能性。原代人心脏干细胞的核型异常在生理（5%）氧的培养中受到抑制，但在培养基中加入抗氧化剂意外地增加了非整倍体。细胞内活性氧水平适度降低生理氧，但显着降低了高剂量的抗氧化剂。心脏干细胞和人类胚胎干细胞中DNA损伤的定量分析显示了一种双相的剂量依赖性：抗氧化剂在低浓度下抑制DNA损伤，但在较高浓度下增强这种损伤。高剂量的抗氧化剂降低了ATM（共济失调毛细血管扩张突变）和其他DNA修复酶的细胞水平，为观察到的效应提供了潜在的机制基础。这些结果表明，需要生理水平的细胞内ROS来激活DNA修复途径以维持干细胞中的基因组稳定性。基因组稳定性的“氧化最适”概念对干细胞生物学和致癌作用具有广泛的意义。
Stem cell cytogenetic abnormalities constitute a roadblock to regenerative therapies. We investigated the possibility that reactive oxygen species (ROS) influence genomic stability in cardiac and embryonic stem cells. Karyotypic abnormalities in primary human cardiac stem cells were suppressed by culture in physiological (5%) oxygen, but addition of antioxidants to the medium unexpectedly increased aneuploidy. Intracellular ROS levels were moderately decreased in physiological oxygen, but dramatically decreased by the addition of high-dose antioxidants. Quantification of DNA damage in cardiac stem cells and in human embryonic stem cells revealed a biphasic dose-dependence: antioxidants suppressed DNA damage at low concentrations, but potentiated such damage at higher concentrations. High-dose antioxidants decreased cellular levels of the ATM (ataxia-telangiectasia mutated) and other DNA repair enzymes, providing a potential mechanistic basis for the observed effects. These results indicate that physiological levels of intracellular ROS are required to activate the DNA repair pathway for maintaining genomic stability in stem cells. The concept of an “oxidative optimum” for genomic stability has broad implications for stem cell biology and carcinogenesis.
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