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

Yoshiharu Muto, Masaaki Nishiyama, Akihiro Nita, Toshiro Moroishi, Keiichi I. Nakayama

研究成果: ジャーナルへの寄稿記事

8 引用 (Scopus)

抄録

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.

元の言語英語
記事番号16114
ジャーナルNature communications
8
DOI
出版物ステータス出版済み - 7 17 2017

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homeostasis
stem cells
Hematopoietic Stem Cells
Stem cells
maintenance
Homeostasis
Iron
Maintenance
iron
Iron Regulatory Protein 2
Oxidative stress
Oxidative Stress
mice
proteins
Stem Cells
Down-Regulation
F-Box Proteins
hematopoietic system
Hematopoietic System
Iron Overload

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

これを引用

Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. / Muto, Yoshiharu; Nishiyama, Masaaki; Nita, Akihiro; Moroishi, Toshiro; Nakayama, Keiichi I.

:: Nature communications, 巻 8, 16114, 17.07.2017.

研究成果: ジャーナルへの寄稿記事

Muto, Yoshiharu ; Nishiyama, Masaaki ; Nita, Akihiro ; Moroishi, Toshiro ; Nakayama, Keiichi I. / Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. :: Nature communications. 2017 ; 巻 8.
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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.",
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