Hematopoietic stem cell quiescence attenuates DNA damage repair and response contributing to age-dependent DNA damage accumulation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55525 | GEO | 2014/05/08
SECONDARY ACCESSION(S): PRJNA239886
REPOSITORIES: GEO
Similar Datasets
Project description:Comprehensive analysis of gene expression in hematopoietic stem and progenitor cells from young and old mice. Gene expression profiling of young and old mouse hematopoietic stem and progenitor cells by Gene Expression Commons system.
2014-05-08 | E-GEOD-55525 | biostudies-arrayexpress
Project description:Most adult stem cells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo. Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizes endogenous stress caused by cellular respiration and DNA replication. We demonstrate that HSC quiescence can also have detrimental effects. We found that HSCs have unique cell-intrinsic mechanisms ensuring their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and strong activation of p53-mediated DNA damage response. We show that quiescent and proliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms. We describe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our results demonstrate that quiescence is a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.
| S-EPMC2924905 | biostudies-literature
Project description:Although hematopoietic stem cells (HSCs) in the bone marrow are in a state of quiescence, they harbor the self-renewal capacity and the pluripotency to differentiate into mature blood cells when needed, which is key to maintain hematopoietic homeostasis. Importantly, HSCs are characterized by their long lifespan ( e. g., up to 60 months for mice), display characteristics of aging, and are vulnerable to various endogenous and exogenous genotoxic stresses. Generally, DNA damage in HSCs is endogenous, which is typically induced by reactive oxygen species (ROS), aldehydes, and replication stress. Mammalian cells have evolved a complex and efficient DNA repair system to cope with various DNA lesions to maintain genomic stability. The repair machinery for DNA damage in HSCs has its own characteristics. For instance, the Fanconi anemia (FA)/BRCA pathway is particularly important for the hematopoietic system, as it can limit the damage caused by DNA inter-strand crosslinks, oxidative stress, and replication stress to HSCs to prevent FA occurrence. In addition, HSCs prefer to utilize the classical non-homologous end-joining pathway, which is essential for the V(D)J rearrangement in developing lymphocytes and is involved in double-strand break repair to maintain genomic stability in the long-term quiescent state. In contrast, the base excision repair pathway is less involved in the hematopoietic system. In this review, we summarize the impact of various types of DNA damage on HSC function and review our knowledge of the corresponding repair mechanisms and related human genetic diseases.
| S-EPMC9909303 | biostudies-literature
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, ?H2AX-foci were examined before and after exposure to ionizing irradiation. Analyzing CD34+ and CD34- stem/progenitor cells we observed an increase of endogenous ?H2AX-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 ?H2AX-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.
| S-EPMC3049780 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti-resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit.
| S-EPMC4832316 | biostudies-literature
Project description:Absorption of ultraviolet radiation (UVR) by DNA leads to the predominant formation of cyclobutane pyrimidine dimers (CPD). Since those CPD are responsible for the driver mutations found in skin cancers, their efficient repair is critical. We previously showed that pre-stimulation of fibroblasts with chronic low doses of UVB (CLUV) increases CPD repair efficiency. Since skin cancers are not arising from dermal fibroblasts, this observation is not directly relevant to cutaneous carcinogenesis. We have now exposed HaCaT keratinocytes to a CLUV irradiation protocol to determine whether this pre-stimulation influences CPD removal rate. Similar to fibroblasts, CLUV treatment leads to the accumulation of residual CPD in keratinocytes, which are not repaired but rather tolerated and diluted through DNA replication. In contrast to fibroblasts, in keratinocytes we find that CLUV pre-treatment reduces CPD removal of newly generated damage without inducing a higher sensitivity to UVR-induced cell death. Using our experimental data, we derived a theoretical model to predict CPD induction, dilution and repair that occur in keratinocytes when chronically UVB-irradiated. Altogether, these results suggest that the accumulation of unrepaired CPD and the reduction in repair efficiency caused by chronic UVB exposure might lead to an increase in skin cancer driver mutations.
| S-EPMC10081739 | biostudies-literature
Project description:Massage therapy is commonly used for the physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. While there is some evidence that massage may relieve pain in injured muscle, the cellular effects remain unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of eleven young, male participants after exercised-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline (rest), immediately after 10 minutes of massage treatment (0h), and after a 2.5 hour period of recovery. We found that massage activated the mechanotransduction signaling pathways FAK and Erk1/2, potentiated mitochondrial biogenesis signaling (nuclear PGC-1α), and mitigated the rise in NFkB (p65) nuclear accumulation caused by muscle trauma. Moreover, in spite of having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines TNF-α and IL-6 and reduced HSP27 phosphorylation, effectively mitigating cellular stress resulting from myofiber injury. In summary, massage therapy appears to be clinically beneficial when administered to acutely damaged skeletal muscle by reducing inflammation and promoting mitochondrial biogenesis. 55 muscle biopsies were used in this study as material to evaluate the effects of massage on gene expression. These biopsies were taken from the vastus lateralis of eleven healthy recreationally active males with full ethical approval at McMaster's university. Each individual had an initial biopsy at rest (baseline), followed by exercist testing for peak aerobic capacity. On a second visit, the individual performed a bout of exhaustive aerobic exercise, prior to recieving a randomized massage treatment to one leg. Immediatley following the exercise, subjects were allowed to recover for 10 minutes, while massage oil was lightly applied to both quadriceps. Then a single leg was randomized to recieve massage treatment for 10 minutes. Subjects then rested for 10 minutes, and one additional biopsies were carried out (on each leg). Two and half hours later (3 hours after the cessation of the exercise bout), 2 more biopsies were taken (one from each leg). This amounted to 5 biopsies from each individual.
2011-11-10 | E-GEOD-33603 | biostudies-arrayexpress
Project description:The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50(S) allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50(S) experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50(S/S) mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50(S/S) is combined with mutations that alter either LSK cell quiescence (myeloid elf-1-like factor/ELF4-deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50(S) pathology. We show that cells from Rad50(S/S) mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of Rad50(S/S) hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50(S/S) mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in Rad50(S/S) mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential.
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Project description:Endogenous and exogenous factors constantly challenge cellular DNA, generating cytotoxic and/or mutagenic DNA adducts. As a result, organisms have evolved different mechanisms to defend against the deleterious effects of DNA damage. Among these diverse repair pathways, direct DNA-repair systems provide cells with simple yet efficient solutions to reverse covalent DNA adducts. In this review, we focus on recent advances in the field of direct DNA repair, namely, photolyase-, alkyltransferase-, and dioxygenase-mediated repair processes. We present specific examples to describe new findings of known enzymes and appealing discoveries of new proteins. At the end of this article, we also briefly discuss the influence of direct DNA repair on other fields of biology and its implication on the discovery of new biology.
| S-EPMC3579392 | biostudies-literature
Project description:Massage therapy is commonly used for the physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. While there is some evidence that massage may relieve pain in injured muscle, the cellular effects remain unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of eleven young, male participants after exercised-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline (rest), immediately after 10 minutes of massage treatment (0h), and after a 2.5 hour period of recovery. We found that massage activated the mechanotransduction signaling pathways FAK and Erk1/2, potentiated mitochondrial biogenesis signaling (nuclear PGC-1α), and mitigated the rise in NFkB (p65) nuclear accumulation caused by muscle trauma. Moreover, in spite of having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines TNF-α and IL-6 and reduced HSP27 phosphorylation, effectively mitigating cellular stress resulting from myofiber injury. In summary, massage therapy appears to be clinically beneficial when administered to acutely damaged skeletal muscle by reducing inflammation and promoting mitochondrial biogenesis.
2011-11-10 | GSE33603 | GEO