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.

中文翻译：

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规范的Wnt /β-Catenin高活性使小鼠造血干细胞和祖细胞对DNA损伤敏感。

衰老的特征在于DNA损伤的积累和干细胞功能的下降，然而，仍然有待阐明限制DNA损伤的干细胞维持的分子机制。在这里，我们在小鼠模型中显示，DNA损伤导致造血干细胞（HSC）中Wnt信号的短暂过度激活，而规范性Wnt /β-catenin信号的高活性使HSC对X射线诱导的DNA损伤敏感。导致具有较低Wnt信号水平的HSC优先维护。研究表明，经典Wnt信号的遗传或化学激活增强了HSC的放射敏感性，而Wnt信号的抑制则降低了它。一起，这些结果表明，Wnt信号传导活性水平介导HSC对DNA损伤诱导的耗竭的敏感性的异质性。这些发现可能与衰老和癌症形成过程中DNA损伤积累的背景下干细胞的分子改变和选择有关。