GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis

• Published in: Cell death & disease Vol. 12; no. 7; p. 706
• Main Authors: Hu, Qian, Zhang, Yifan, Lou, Huiling, Ou, Zexian, Liu, Jin, Duan, Wentao, Wang, Hao, Ge, Yuanlong, Min, Junxia, Wang, Fudi, Ju, Zhenyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/31; 631/443; 631/80; 692/308/2171; 82/80; Animals; Antibodies; Antioxidants - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cells, Cultured; Disease Models, Animal; Female; Ferroptosis; Ferroptosis - drug effects; Glutathione peroxidase; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - enzymology; Hematopoietic Stem Cells - pathology; Immunology; Life Sciences; Lipid metabolism; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Progenitor cells; Stem cell transplantation; Stem cells; Tumorigenesis; Vitamin E; Vitamin E - pharmacology; Vitamin E Deficiency - drug therapy; Vitamin E Deficiency - enzymology; Vitamin E Deficiency - genetics; Vitamin E Deficiency - pathology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04008-9

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx 4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.