Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
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DOI：
10.1038/nm1388
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发表时间：
2006-04-01
期刊：
影响因子：
82.9
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Ito, K;Hirao, A;Suda, T
造血干细胞(HSCs)经历自我更新的细胞分裂，并在其一生中维持血液生产(1)。适当控制HSC的自我更新是维持造血内环境稳定的关键。在这里，我们表明，活化的p38MAPK的反应，增加水平的活性氧(ROS)限制了HSCs在体内的寿命。在ATM(-/-)小鼠中，ROS水平的升高诱导HSC特异性的p38MAPK磷酸化，同时伴随着HSC静止维持的缺陷。抑制p38MAPK可以挽救ROS诱导的HSC再生能力和维持HSC静止的缺陷，表明ROS-p38MAPK通路有助于干细胞群的耗竭。此外，在一系列移植实验中，延长抗氧化剂或p38 MAPK抑制剂的治疗延长了来自野生型小鼠的HSC的寿命。这些数据表明，p38MAPK的失活可以保护HSCs免受自我更新能力的丧失。我们对限制HSC寿命的分子机制的表征可能会导致对人类疾病的有益治疗。
Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime(1). Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS- p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.