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

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861 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)446-451
Number of pages6
JournalNature medicine
Volume12
Issue number4
DOIs
Publication statusPublished - Apr 1 2006

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p38 Mitogen-Activated Protein Kinases
Hematopoietic Stem Cells
Stem cells
Reactive Oxygen Species
Maintenance
Defects
Phosphorylation
Cell Division
Homeostasis
Stem Cells
Antioxidants
Transplantation
Blood
Chemical activation
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., ... 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

Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. / Ito, Keisuke; Hirao, Atsushi; Arai, Fumio; Takubo, Keiyo; Matsuoka, Sahoko; Miyamoto, Kana; Ohmura, Masako; Naka, Kazuhito; Hosokawa, Kentaro; Ikeda, Yasuo; Suda, Toshio.

In: Nature medicine, Vol. 12, No. 4, 01.04.2006, p. 446-451.

Research output: Contribution to journalArticle

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, vol. 12, no. 4, pp. 446-451. https://doi.org/10.1038/nm1388
Ito, Keisuke ; Hirao, Atsushi ; Arai, Fumio ; Takubo, Keiyo ; Matsuoka, Sahoko ; Miyamoto, Kana ; Ohmura, Masako ; Naka, Kazuhito ; Hosokawa, Kentaro ; Ikeda, Yasuo ; Suda, Toshio. / Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. In: Nature medicine. 2006 ; Vol. 12, No. 4. pp. 446-451.
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