Dataset Information

High Canonical Wnt/?-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage.

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/?-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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6987068 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

High Canonical Wnt/β-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage.

Wang Yiting Y Cui Hui H Tao Si S Zeng Ting T Wu Jianying J Tao Zhendong Z Zhang Liu L Zou Bing B Chen Zhiyang Z Garside George B GB Tang Duozhuang D

Stem cell reviews and reports 20200201 1

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 mai ...[more]

PMID: 31797147

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Project description:BackgroundAccumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of aging. Here we tested this hypothesis in healthy individuals of different ages by examining unrepaired DNA double-strand breaks (DSBs) in hematopoietic stem/progenitor cells matured in their physiological microenvironment.Methodology/principal findingsTo asses DNA damage accumulation and repair capacities, γH2AX-foci were examined before and after exposure to ionizing irradiation. Analyzing CD34+ and CD34- stem/progenitor cells we observed an increase of endogenous γH2AX-foci levels with advancing donor age, associated with an age-related decline in telomere length. Using combined immunofluorescence and telomere-fluorescence in-situ hybridization we show that γH2AX-foci co-localize consistently with other repair factors such as pATM, MDC1 and 53BP1, but not significantly with telomeres, strongly supporting the telomere-independent origin for the majority of foci. The highest inter-individual variations for non-telomeric DNA damage were observed in middle-aged donors, whereas the individual DSB repair capacity appears to determine the extent of DNA damage accrual. However, analyzing different stem/progenitor subpopulations obtained from healthy elderly (>70 years), we observed an only modest increase in DNA damage accrual, most pronounced in the primitive CD34+CD38(-)-enriched subfraction, but sustained DNA repair efficiencies, suggesting that healthy lifestyle may slow down the natural aging process.Conclusions/significanceBased on these findings we conclude that age-related non-telomeric DNA damage accrual accompanies physiological stem cell aging in humans. Moreover, aging may alter the functional capacity of human stem cells to repair DSBs, thereby deteriorating an important genome protection mechanism leading to exceeding DNA damage accumulation. However, the great inter-individual variations in middle-aged individuals suggest that additional cell-intrinsic mechanisms and/or extrinsic factors contribute to the age-associated DNA damage accumulation.

Dataset Information

High Canonical Wnt/?-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage.

Publications

High Canonical Wnt/β-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage.

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