Blood 118, 2941–2950 (2011)

Reactive oxygen species (ROS) and DNA repair defects are known to limit the regenerative potential of hematopoietic stem cells (HSCs), which is necessary to replenish mature blood cells. Yahata et al. now provide evidence that these two insults to HSCs are related: long-term production of ROS leads to the accumulation of DNA damage and exhausts HSCs. The authors demonstrated that human HSCs serially transplanted into mice gradually lost their proliferative capacity and accumulated marks of DNA damage, such as γ-H2AX foci. ROS production increased with each serial transplant, and ROShigh cells lost their repopulation potential by the third transplant. HSCs with elevated ROS levels—induced by inhibition of glutathione synthetase with buthionine sulfoximine (BSO)—had increased numbers of γ-H2AX foci, expressed DNA damage-response proteins and showed diminished repopulating capacity. The authors further demonstrated that HSCs are more sensitive to ROS production than progenitor cells from the same lineage, showing that inhibition with BSO yielded comparable amounts of ROS in both cell types. The HSCs, however, showed more cell-cycle arrest as well as faster and more persistent accumulation of γ-H2AX foci. Inhibition of ROS production with an antioxidant blocked the accumulation of BSO-induced DNA damage and improved the self-renewal capacity of HSCs. Taken together, these data indicate that ROS play a causative role in the accumulation of DNA damage in HSCs and have implications for the renewal capacity of these cells.