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

A Corrigendum to this article was published on 01 January 2010

This article has been updated


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.

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Figure 1: Increased ROS abrogates the reconstituting capacity of HSCs.
Figure 2: HSC-specific activation of p38 MAPK induced by ROS.
Figure 3: ROS–p38 MAPK induces exhaustion of HSCs.
Figure 4: Inactivation of p38 MAPK extends the lifespan of HSCs in serial transplantation.

Change history

  • 07 January 2010

    In the version of this article initially published, two micrographs in Figure 2c, corresponding to the conditions BSO(–) Lineage– and BSO(+) Lineage–, were incorrect. These micrographs have been replaced with the correct micrographs in the HTML and PDF versions of the article.


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We thank P.J. McKinnon for providing Atm+/− mice and H. Saya for discussion, H. Ichijo and K. Takeda for providing Map3k5 cDNA, T. Kitamura for providing the retrovirus vector pMY-IRES-EGFP and A. Ono and K. Murakami for technical support. K.I. was supported by a grant-in-aid for Young Scientists from the Ministry of Education, Science, Sports, and Culture, Japan. A.H. was supported by a grant-in-aid for the Stem Cell Research from the Ministry of Education, Science, Sports, and Culture, Japan. T.S. was supported by a grant-in-aid for Specially Promoted Research from Ministry of Education, Science, Sports, and Culture, Japan.

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Correspondence to Atsushi Hirao or Toshio Suda.

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Supplementary information

Supplementary Fig. 1

Effect of increased ROS on HSCs and progenitor cells. (PDF 4273 kb)

Supplementary Fig. 2

Atm−/− HSCs are highly sensitive to ROS elevation in terms of p38 MAPK activation. (PDF 1639 kb)

Supplementary Fig. 3

Treatment with a p38 MAPK inhibitor rescues defective HSC function in Atm−/− mice. (PDF 5444 kb)

Supplementary Fig. 4

Elevation of ROS level and p16Ink4a/p19Arf expression in KSL cells during aging and serial transplantation. (PDF 3302 kb)

Supplementary Fig. 5

In vitro treatment with a p38 MAPK inhibitor restores BSO-induced defective repopulating capacity of HSCs. (PDF 2665 kb)

Supplementary Table 1

List of RT-PCR primers used in this study. (PDF 5052 kb)

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Ito, K., Hirao, A., Arai, F. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12, 446–451 (2006).

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