Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration.
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.
Department of Pharmacology, University of California at San Diego School of Medicine, La Jolla, California 92093, USA;
William
W
Lento
Takahiro
T
Ito
Chen
C
Zhao
Jeffrey R
JR
Harris
Wei
W
Huang
Chen
C
Jiang
Kouros
K
Owzar
Sadhna
S
Piryani
Luigi
L
Racioppi
Nelson
N
Chao
Tannishtha
T
Reya
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D053208:Kaplan-Meier Estimate; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics* / Q000528:radiation effects; D011832:Radiation Injuries / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000528:radiation effects; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D051176:beta Catenin; D005472:Fluorouracil
Wnt signaling; hematopoietic stem cells; oxidative stress; regeneration; β-catenin