Abstract
Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation.
Highlights
Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress
Analysis of public data sets revealed that downregulation of F-box and leucine-rich repeat protein 5 (FBXL5) expression was associated with myelodysplastic syndrome (MDS), a disease characterized by bone marrow (BM) failure
CITED2 was shown to control the proliferation of mouse embryonic fibroblasts by promoting expression of the Polycomb group genes Bmi[1] and Mel[18] as well as to selectively maintain adult HSC function at least in part through regulation of p16 and p53
Summary
Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Clinical evidence suggests that systemic iron overload has a suppressive effect on hematopoiesis in individuals with MDS or aplastic anaemia, and that iron-chelation therapy often improves this situation[13,14,15] These observations imply that hematopoietic failure promotes systemic iron overload, which in turn exacerbates hematopoietic failure, with the two conditions forming a vicious cycle. Oxidative stress was found to be increased in bone marrow (BM) cells of patients with iron overload, and the impaired hematopoietic function of these individuals was partially rescued by treatment with an antioxidant or iron chelator, suggestive of the initial presence of ROS-induced cellular injury[16]. The molecular mechanisms underlying hematopoietic suppression by systemic iron overload in patients as well as the cell-autonomous effect of cellular iron overload on HSC stemness have remained largely unknown
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