Carbon Monoxide Protects Neural Stem Cells Against Iron Overload by Modulating the Crosstalk Between Nrf2 and NF-κB Signaling.

Although accumulating evidences have demonstrated pro-survival effects of CO against various insults, the precise mechanism explaining how neural stem cells (NSCs) are protected by CO also remains largely unknown. Here we report CO pro-survival effect on NSCs against iron overload was comparable to that obtained with pharmacological inhibitors of reactive oxygen species (ROS). Its pro-survival effect was accompanied by the inhibition of ROS and subsequent inhibition of NF-κB which is mediated through nuclear factor erythroid 2-related factor 2 (Nrf2), in that activation of Nrf2 by CO inhibited ROS via up-regulation of NQO-1 while down-regulation of Nrf2 reversed the pro-survival effect of CO both in vitro and in vivo. CO-mediated preconditioning results in Nrf2 up-regulation and NF-κB inhibition, suggesting that these two pathways act in an inverse manner to maintain redox homeostasis. Our findings revealed CO preconditioning as a promising treatment strategy to improve efficacy of NSCs transplantation after hemorrhagic stroke.