Bmi1 Confers Resistance to Oxidative Stress on Hematopoietic Stem Cells

<div><h3>Background</h3><p>The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of <em>Bmi1</em>, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of <em>Bmi1</em> on HSCs <em>in vivo</em> remained to be precisely addressed.</p> <h3>Methodology/Principal findings</h3><p>In this study, we generated a mouse line where <em>Bmi1</em> can be conditionally overexpressed under the control of the endogenous <em>Rosa26</em> promoter in a hematopoietic cell-specific fashion (<em>Tie2-Cre;R26Stop^FLBmi1</em>). Although overexpression of <em>Bmi1</em> did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during <em>ex vivo</em> culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of <em>Bmi1</em> had no effect on DNA damage response triggered by ionizing radiation. In contrast, <em>Tie2-Cre;R26Stop^FLBmi1</em> HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of <em>Bmi1</em> had no impact on the level of intracellular reactive oxygen species (ROS).</p> <h3>Conclusions/Significance</h3><p>Our findings demonstrate that overexpression of <em>Bmi1</em> confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.</p>