Ito Keisuke, Hirao Atsushi, Arai Fumio, Takubo Keiyo, Matsuoka Sahoko, Miyamoto Kana, Ohmura Masako, Naka Kazuhito, Hosokawa Kentaro, Ikeda Yasuo, Suda Toshio
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
Nat Med. 2006 Apr;12(4):446-51. doi: 10.1038/nm1388. Epub 2006 Mar 26.
Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. 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.
造血干细胞（HSCs）进行自我更新的细胞分裂，并在其生命周期内维持血液生成。对造血干细胞自我更新的适当控制对于维持造血稳态至关重要。在这里，我们表明，响应活性氧（ROS）水平升高而激活的p38丝裂原活化蛋白激酶（MAPK）会限制体内造血干细胞的寿命。在Atm基因敲除小鼠中，ROS水平的升高会诱导造血干细胞特异性的p38 MAPK磷酸化，并伴有造血干细胞静止维持缺陷。抑制p38 MAPK可挽救ROS诱导的造血干细胞再增殖能力缺陷和造血干细胞静止维持缺陷，表明ROS-p38 MAPK途径导致干细胞群体耗竭。此外，在连续移植实验中，用抗氧化剂或p38 MAPK抑制剂进行长期治疗可延长野生型小鼠造血干细胞的寿命。这些数据表明，p38 MAPK的失活可保护造血干细胞免于自我更新能力的丧失。我们对限制造血干细胞寿命的分子机制的表征可能会为人类疾病带来有益的治疗方法。
