Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells

Keisuke Ito, Atsushi Hirao, Fumio Arai, Keiyo Takubo, Sahoko Matsuoka, Kana Miyamoto, Masako Ohmura, Kazuhito Naka, Kentaro Hosokawa, Yasuo Ikeda, Toshio Suda

研究成果: Article

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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.

元の言語English
ページ(範囲)446-451
ページ数6
ジャーナルNature medicine
12
発行部数4
DOI
出版物ステータスPublished - 2006 4 1

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

これを引用

Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., & Suda, T. (2006). Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature medicine, 12(4), 446-451. https://doi.org/10.1038/nm1388