Id1 Ablation Protects Hematopoietic Stem Cells from Stress-Induced Exhaustion and Aging

Defining mechanisms that maintain tissue stem cells during homeostasis and stress is important for improving tissue regeneration and repair, cancer and aging. Inhibitor of DNA binding protein (Id1) is induced in hematopoietic stem cells (HSCs) by proinflammatory cytokines that promote HSC proliferation and differentiation in vitro and in vivo, suggesting that Id1 may function during stress hematopoiesis. Id1-/- HSCs show increased self-renewal in serial bone marrow transplantation (BMT) assays, which is correlated with decreased proliferation, mitochondrial biogenesis, and ROS production. As a result, Id1-/- HSCs harbor less DNA damage, show increased quiescence and reduced aging. Mechanistically, we show that cytokines and other proinflammatory stimuli present in the hematopoietic microenvironment after γ-irradiation induce Id1 expression. Id1-/- HSCs fail to properly respond to cytokine-induced proliferation, suggesting that HSC exhaustion is mediated, in part, by chronic proliferative stress. Id1-/- HSCs are protected from other chronic proliferative stresses including chronic genotoxic and inflammatory stress, and aging. Thus, targeting Id1 inhibition may be therapeutically useful to improve HSC survival and function during BMT, chronic stress and aging. Funded by FNLCR Contract HHSN261200800001E