Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration
- William Lento1,2,3,4,
- Takahiro Ito1,2,
- Chen Zhao3,
- Jeffrey R. Harris4,
- Wei Huang4,
- Chen Jiang5,
- Kouros Owzar5,
- Sadhna Piryani4,
- Luigi Racioppi4,6,
- Nelson Chao4 and
- Tannishtha Reya1,2,3,7,8
- 1Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla, California 92093, USA;
- 2Sanford Consortium for Regenerative Medicine, La Jolla, California 92093, USA;
- 3Department of Pharmacology and Cancer Biology,
- 4Department of Medicine, Division of Hematological Malignancies and Cellular Therapy,
- 5Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA;
- 6Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy;
- 7Moores Cancer Center, University of California at San Diego School of Medicine, La Jolla, California 92093, USA
Abstract
Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. β-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking β-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, β-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on β-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.
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Footnotes
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↵8 Corresponding author
E-mail treya{at}ucsd.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.231944.113.
- Received October 1, 2013.
- Accepted March 26, 2014.
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