期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 1-13出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms16114
关键词
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资金
- KAKENHI grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan [25221303, 26640080]
- Grants-in-Aid for Scientific Research [15K06835, 17H05953, 16H01341, 26640080] Funding Source: KAKEN
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.
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