Nature Medicine
- 12, 446 - 451 (2006)
Published online: 26 March 2006; | doi:10.1038/nm1388
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cellsKeisuke Ito1, 2, 5, Atsushi Hirao1, 3, 4, 5, Fumio Arai1, Keiyo Takubo1, Sahoko Matsuoka1, 2, Kana Miyamoto1, Masako Ohmura1, 3, Kazuhito Naka3, Kentaro Hosokawa1, Yasuo Ikeda2 & Toshio Suda11
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. 2
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. 3
Division of Molecular Genetics, Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-0934, Japan. 4
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. 5
These authors contributed equally to this work.
Correspondence should be addressed to Atsushi Hirao ahirao@kenroku.kanazawa-u.ac.jp or Toshio Suda sudato@sc.itc.keio.ac.jp Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime1. 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
