An essential role of FBXL5-mediated cellular iron homeostasis in the maintenance of hematopoietic stem cells

Hematopoietic stem cells (HSCs) are maintained in the hypoxic niche so as to limit oxidative stress. Although iron is a major factor to evoke oxidative stress, the importance of cellular iron homeostasis in HSCs has been unrecognized. We now demonstrate that iron regulation mediated by FBXL5 is required for the self-renewal capability of HSCs. Conditional ablation of Fbxl5 gene in mouse HSCs resulted in cellular iron overload, leading to the reduction in the number of HSCs. Bone-marrow transplantation experiments revealed that FBXL5-deficient HSCs were unable to reconstitute the hematopoietic system as a result of stem cell exhaustion. Transcriptomic analysis showed abnormal activation of oxidative stress response as well as cell cycle in HSCs. Suppression of IRP2 activity in FBXL5-deficient HSCs restored the stem cell function, suggesting that IRP2 is potentially a novel therapeutic target of stem cell diseases such as myelodysplastic syndrome, which is associated with FBXL5 downregulation in humans. 3000 HSCs were purified as c-Kit+Sca-1+Lin–CD150+CD48– bone marrow cells from 3 control mice and 3 mice with conditional FBXL5 knockout on C57Bl/6 background.