The accumulation of DNA damage in hematopoietic stem cells (HSCs) is a hallmark of aging and a major contributor to functional degeneration and malignant transformation. In Nature, Walter et al. show that DNA damage in mice is a direct consequence of the exit of HSCs from their homeostatic quiescent state in response to physiological stress, such as infection or chronic blood loss. A range of stimuli that induce the entry of long-term HSCs into the cell cycle induce new DNA damage, which is dependent on enhanced mitochondrial metabolic activity and ROS production but seems to be independent of exogenous proinflammatory cytokines. Cumulative rounds of replicative stress in wild-type mice precipitate a phenotype in HSCs similar to aging, such as depletion of transplantable HSCs and a strong myeloid bias after reconstitution in recipient mice. These observations link 'stress hematopoiesis' with the functional decline of HSCs.

Nature (18 February 2015) doi:10.1038/nature14131