Abstract
BackgroundStem cells of intensely regenerative tissues are susceptible to cellular damage. Although the response to this process in hematopoietic stem cells (HSCs) is crucial, the mechanisms by which hematopoietic homeostasis is sustained are not completely understood. Aging increases reactive oxygen species (ROS) levels and inflammation, which contribute to increased proliferation, senescence and/or apoptosis, leading to self-renewal premature exhaustion. In this study, we assessed ROS production, DNA damage, apoptosis, senescence and plasticity in young, middle and aged (2-, 12- and 24-month-old, respectively) C57BL/6 J mice.ResultsAged HSCs showed an increase in intracellular superoxide anion (1.4-fold), hydrogen peroxide (2-fold), nitric oxide (1.6-fold), peroxynitrite/hidroxil (2.6-fold) compared with young cells. We found that mitochondria and NADPHox were the major sources of ROS production in the three groups studied, whereas CYP450 contributed in middle and aged, and xanthine oxidase only in aged HSCs. In addition, we observed DNA damage and apoptosis in the middle (4.2- and 2-fold, respectively) and aged (6- and 4-fold, respectively) mice; aged mice also exhibited a significantly shorter telomere length (−1.8-fold) and a lower expression of plasticity markers.ConclusionThese data suggest that aging impairs the functionality of HSCs and that these age-associated alterations may affect the efficacy of aged HSC recovery and transplantation.
Highlights
Stem cells of intensely regenerative tissues are susceptible to cellular damage
Aging stimulates cell cycling and myeloid skewing To evaluate the impact of aging on hematopoietic stem cells (HSCs) (KTLS/CD133+), we determined the number of cells and proliferation by cell cycle analysis (Table 1) and complete blood count (CBC) (Table 2)
Sources of reactive oxygen species (ROS) and antioxidant enzyme capacity in HSCs Considering that little is known about which pathways are involved in ROS production by HSCs and the stimuli of cell intrinsic alterations that trigger HSC aging, we evaluated the relative contributions of different pathways, which could lead to augmented ROS production and/or the loss of antioxidant capacity
Summary
Stem cells of intensely regenerative tissues are susceptible to cellular damage. the response to this process in hematopoietic stem cells (HSCs) is crucial, the mechanisms by which hematopoietic homeostasis is sustained are not completely understood. Stem cells are important for the maintenance of functional tissues and organs and have the abilities to selfrenew and replace damaged cells [1] This finely tuned regulatory system may become altered with aging [2]. Some researchers have highlighted the impact of aging on HSCs, the molecular events that trigger the biology of aging remain unclear In both mice and humans, researchers have profiled the expression of genes involved in genomic integrity and transcriptional regulation demonstrating that the direct or epigenetic modulation of these genes (e.g. p53, p66shc, FOXO3, SIRT1, NF-κB) are consequence of high levels of reactive oxygen species (ROS) in different diseases [7, 8]. It is known that high ROS can inhibit SIRT1 and
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