Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Weissman, I.L. et al. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).

    Article  CAS  Google Scholar 

  2. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    Article  CAS  Google Scholar 

  3. Schriner, S.E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    Article  CAS  Google Scholar 

  4. Kujoth, G.C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    Article  CAS  Google Scholar 

  5. Allsopp, R.C. et al. Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat. Med. 9, 369–371 (2003).

    Article  CAS  Google Scholar 

  6. Allsopp, R.C., Cheshier, S. & Weissman, I.L. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J. Exp. Med. 193, 917–924 (2001).

    Article  CAS  Google Scholar 

  7. Griffith, O. Depletion of glutathione by inhibition of biosynthesis. Methods Enzymol. 77, 59–63 (1981).

    Article  CAS  Google Scholar 

  8. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  Google Scholar 

  9. Park, I.K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  Google Scholar 

  10. Wen-Sheng, W. ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a. Oncogene 22, 955–963 (2003).

    Article  Google Scholar 

  11. Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131–144 (2003).

    Article  CAS  Google Scholar 

  12. Bulavin, D.V. et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat. Genet. 36, 343–350 (2004).

    Article  CAS  Google Scholar 

  13. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  Google Scholar 

  14. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).

    Article  CAS  Google Scholar 

  15. Harrison, D.E. Normal function of transplanted marrow cell lines from aged mice. J. Gerontol. 30, 279–285 (1975).

    Article  CAS  Google Scholar 

  16. Harrison, D.E. & Doubleday, J.W. Normal function of immunologic stem cells from aged mice. J. Immunol. 114, 1314–1317 (1975).

    CAS  PubMed  Google Scholar 

  17. Tobiume, K. et al. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2, 222–228 (2001).

    Article  CAS  Google Scholar 

  18. Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).

    Article  CAS  Google Scholar 

  19. Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).

    Article  CAS  Google Scholar 

  20. Verma, A. et al. Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia. J. Immunol. 168, 5984–5988 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Atsushi Hirao or Toshio Suda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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). https://doi.org/10.1038/nm1388

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1388

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing