Abstract
Aging is characterized by the accumulation of DNA damage and a decrease in stem cell functionality, yet molecular mechanisms that limit the maintenance of stem cells in response to DNA damage remain to be delineated. Here we show in mouse models that DNA damage leads to a transient over-activation of Wnt signaling in hematopoietic stem cells (HSCs), and that high activity of canonical Wnt/β-catenin signaling sensitizes HSCs to DNA damage induced by X-irradiation which results in preferential maintenance of HSCs with low levels of Wnt signaling. The study shows that genetic or chemical activation of canonical Wnt signaling enhances radiosensitivity of HSCs while inhibition of Wnt signaling decreases it. Together, these results indicate that levels of Wnt signaling activity mediate heterogeneity in the sensitivity of HSCs to DNA damage induced depletion. These findings could be relevant for molecular alterations and selection of stem cells in the context of DNA damage accumulation during aging and cancer formation.