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.
Highlights
Functionality of adult stem cells decreases during aging [1–3], which is thought to contribute to impairments in tissue maintenance and regeneration
These results indicate that irradiation triggers activation of DNA damage signaling and canonical Wnt-signaling, but that high levels of Wnt-signaling activity could not be maintained in the hematopoietic stem cells (HSCs) pool in response to DNA damage
The current study provides experimental evidence that the level of canonical Wnt-signaling activity mediates the sensitivity of hematopoietic stem and progenitor cells (HSPCs) to DNA damage
Summary
Functionality of adult stem cells decreases during aging [1–3], which is thought to contribute to impairments in tissue maintenance and regeneration. The underlying mechanisms involve age-dependent alterations in self-renewal pathways as well as the accumulation of DNA damage in stem cells [2, 4–7]. Possible connections between DNA damage induced aging and stem cell self-renewal pathways remain to be delineated. Loss-of-function studies show that the canonical Wnt/β-catenin signaling pathway, one of the essential selfrenewal pathways, is required for the normal functioning of adult hematopoietic stem and progenitor cells (HSPCs) [8–10]. The over-activation of canonical Wnt signaling was detrimental for HSC maintenance as it causes premature exhaustion of HSCs [11–14]. Derangement of Wnt-signaling activity contributes to impairment of stem cell function in aging tissues [15–17].
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