You are hereApril 27, 2015 | Haematopoetic Stem Cells
Stressed out HSCs Wake Up to DNA Damage
Review of “Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells” from Nature by Stuart P. Atkinson
DNA damage in haematopoietic stem cells (HSCs) has long been linked to age-related tissue degeneration and tumorigenesis , but to this day, the source of this damage has not been clearly identified. In a study recently published in Nature, researchers from the laboratory of Michael D. Milsom have demonstrated an increase in DNA damage accumulation when HSCs exit from their normally resting quiescent state in response to states of physiological stress which necessitate blood forming responses, such as infection or blood loss .
The researchers first utilized polyinosinic:polycytidylic acid (pI:pC) injection in mice to mimic a viral infection, which leads to the exit of long-term (LT)-HSCs from quiescence in vivo . Isolation and analysis of these activated cycling LT-HSCs found increased levels of various signs of DNA damage: DNA double-strand breaks (DSBs) and single-strand breaks, nuclear foci of H2AX, and both 53BP1 and RAD51 foci indicative of DNA damage repair efforts. Researchers also found similar findings for other physiological stimuli including treatment with IFN-, granulocyte colony-stimulating factor (G-CSF), Thrombopoietin (TPO) or by serial bleeding, so linking physiological stress signals to HSC-activation/cell cycle entry and DNA damage.
To assess how DNA damage occurs in this context, the group asked if mitochondrial reactive oxygen species (ROS) may play a role. Upon exit from quiescence, mitochondrial membrane potential increased in LT-HSCs (indicative of higher metabolic activity), and this correlated to significant increases in cytoplasmic H2O2, the mitochondrial glutathione redox potential, and the levels of the ROS-specific 8-oxo-29-deoxyguanosine (8-Oxo-dG) DNA lesion in LT-HSCs. Furthermore, overexpression of ROS-detoxifying enzymes reduced this stress-induced increase in DNA-DSBs in LT-HSCs, further strengthening the link between higher cell-cycle exit, higher mitochondrial metabolism, and DNA damage.
In order to repair DNA damage repair (DDR), LT-HSCs engage a Fanconi anemia (FA) pathway-mediated DDR, a system whose inactivation leads to a reduction in the genomic integrity of HSCs leading to an increased risk of hematological tumorigenesis . In mice with a targeted deletion of the FA pathway gene Fanca, applied physiological stress induced higher levels of levels of DNA damage in LT-HSCs, as well as the previously described mitochondrial metabolism phenotypes, as compared to the wild type. Loss of a functional Fanconi anemia DDR pathway also led to increased cell death, and so inefficient repair of replicative DNA damage may result in LT-HSC depletion over time, and so may lead to bone marrow failure. Indeed, long-term physiological stress (4 weeks) inhibited the entry of Fanca-depleted LT-HSCs into quiescence, and while wild type LT-HSCs did display a two-fold reduction in their repopulating activity, Fanca-depleted LT-HSCs displayed a four-fold decrease, suggesting an additional loss of functionality. At this stage, the observed functional impairment did not alter levels of mature haematopoietic cells or progenitors, but after sustained rounds of prolonged stress treatments, the Fanca depleted mice presented with severe aplastic anemia. The bone marrow was almost completely depleted of the entire HSC and progenitor compartment, and even wild type mice under prolonged stress presented with a significant depletion of transplantable HSCs, highlighting a strong correlation between stress, DNA damage accumulation, and accelerated HSC dysfunction.
The demonstration of the novel link between physiologic stress, DNA damage in stem cells, and HSC dysfunction over time may now allow us to identify strategies to inhibit damage to stem cells and in doing so mitigate the symptoms of again and prevent tumorigenesis.
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