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Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells

Author

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  • Yoshiharu Muto

    (Medical Institute of Bioregulation, Kyushu University)

  • Masaaki Nishiyama

    (Medical Institute of Bioregulation, Kyushu University)

  • Akihiro Nita

    (Medical Institute of Bioregulation, Kyushu University)

  • Toshiro Moroishi

    (Medical Institute of Bioregulation, Kyushu University)

  • Keiichi I. Nakayama

    (Medical Institute of Bioregulation, Kyushu University)

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.

Suggested Citation

  • Yoshiharu Muto & Masaaki Nishiyama & Akihiro Nita & Toshiro Moroishi & Keiichi I. Nakayama, 2017. "Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16114
    DOI: 10.1038/ncomms16114
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    Cited by:

    1. Yu-Jung Tseng & Yuki Kageyama & Rebecca L. Murdaugh & Ayumi Kitano & Jong Hwan Kim & Kevin A. Hoegenauer & Jonathan Tiessen & Mackenzie H. Smith & Hidetaka Uryu & Koichi Takahashi & James F. Martin & , 2024. "Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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