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
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
Weissman, I.L. et al. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).
Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).
Schriner, S.E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).
Kujoth, G.C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).
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).
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).
Griffith, O. Depletion of glutathione by inhibition of biosynthesis. Methods Enzymol. 77, 59–63 (1981).
Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).
Park, I.K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).
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).
Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131–144 (2003).
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).
Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).
Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).
Harrison, D.E. Normal function of transplanted marrow cell lines from aged mice. J. Gerontol. 30, 279–285 (1975).
Harrison, D.E. & Doubleday, J.W. Normal function of immunologic stem cells from aged mice. J. Immunol. 114, 1314–1317 (1975).
Tobiume, K. et al. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2, 222–228 (2001).
Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
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).
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
Corresponding authors
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1388
This article is cited by
-
Effects of fine particulate matter on bone marrow-conserved hematopoietic and mesenchymal stem cells: a systematic review
Experimental & Molecular Medicine (2024)
-
Functions and regulatory mechanisms of resting hematopoietic stem cells: a promising targeted therapeutic strategy
Stem Cell Research & Therapy (2023)
-
Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma
Cell Death & Disease (2023)
-
Prion infection modulates hematopoietic stem/progenitor cell fate through cell-autonomous and non-autonomous mechanisms
Leukemia (2023)
-
Alteration in apoptosis and ataxia telangiectasia mutated (ATM) gene expression in mesenchymal stem cells in patients with idiopathic acquired aplastic anemia
Comparative Clinical Pathology (2023)