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Increased endogenous reactive oxygen species normalizes proliferation defects of Bmi1 heterozygous knockout neural stem cells

Supplemental Digital Content is available in the text. Objectives The Bmi1gene, one of transcriptional suppressor genes in multi-comb family, maintains proliferation of neural stem cells (NSCs) and redox homeostasis. However, heterozygous deletion of the Bmi1 gene (Bmi1+/−) does not reduce the proliferative ability of NSCs. The aim of the present study was to reveal the underlying mechanism of this phenotype. Methods NSCs derived from the cortex of newborn Bmi1+/− and wild-type (WT) mice were treated with different concentrations of hydrogen peroxide (H2O2) and antioxidant N-acetyl-L-cysteine (NAC) for 24 h followed by analyses of NSC proliferation and oxidative stress-related indexes. Results The levels of reactive oxygen species (ROS) of Bmi1+/−-NSCs were slightly higher than that of WT-NSCs at baseline. H2O2 increased ROS and NAC reduced ROS in a concentration-dependent pattern, but the change was significantly greater in Bmi1+/−-NSCs than WT-NSCs. The proliferation and self-renewal ability of Bmi1+/−-NSCs and WT-NSCs were comparable in a basic state. After 1 μM H2O2 treatment, Brdu incorporation ratio, cell viability, total antioxidant capacity (T-AOC) and total superoxide dismutase activity were increased slightly in WT-NSCs, but decreased in Bmi1+/−-NSCs. H2O2 at 10 μM decreased proliferation and self-renewal ability of both genotype NSCs, with greater effect in Bmi1+/−. After treatment with 1 mM NAC, the number and diameter of neurospheres, Brdu incorporation rate, cell viability, T-AOC and total superoxide dismutase activity of Bmi1+/−-NSCs were lower than those of WT-NSCs. Conclusion These results suggest that Bmi1+/−-NSCs exhibit normal proliferation and self-renewal due to a slight increase in ROS, but are more vulnerable to changes in redox status.