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Pretreatment of Mouse Neural Stem Cells with Carbon Monoxide-Releasing Molecule-2 Interferes with NF-κB p65 Signaling and Suppresses Iron Overload-Induced Apoptosis

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Abstract

Neural stem cell (NSC) transplantation is a promising approach to repair the damaged brain after hemorrhagic stroke; however, it is largely limited by the poor survival of donor cells. Breakdown products of the hematoma and subsequent iron overload contribute to the impairment of survival of neural cells. There is little information regarding the mechanism involved in the death of grafted cells. Furthermore, therapeutic research targeted to improving the survival of grafted neural stem cells (NSCs) is strikingly lacking. Here, we showed that iron overload induced apoptosis of C17.2 cells, a cell line originally cloned from mouse NSCs and immortalized by v-myc. Pretreatment with carbon monoxide-releasing molecule-2 (CORM-2) markedly protected C17.2 cells against iron overload in a dose-dependent manner. Moreover, CORM-2 interfered with NF-κB signaling, including inhibition of nuclear translocation and down-regulation of NF-κB p65. TUNEL staining showed that preconditioning C17.2 cells with CORM-2 enhanced their resistance to apoptosis induced by iron overload, which was concomitant with down-regulation of the pro-apoptotic proteins (Bax and cleaved caspase-3) and up-regulation of the anti-apoptotic protein Bcl2. The protective effect of CORM-2 could be simulated by BAY11-7082, a special inhibitor of NF-κB p65. These results provide a novel and effective strategy to enhance the survival of NSCs after transplantation and, therefore, their efficacy in repairing brain injury due to hemorrhagic stroke.

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Acknowledgments

The project was financially supported by The National Natural Science Foundation of China (No. 81471176; 81301045) and SJTU Medicine-Engineering Research Fund (Grant No. YG2012MS06; YG2014QN17). We thank Prof. Jin WL for supplying us with the C17.2 cell line.

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Authors and Affiliations

  1. Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Zhengxing Xie, Zhenwen Cui, Baofeng Wang, Zhihong Zhong, Yuhao Sun, Qingfang Sun & Liuguan Bian

  2. Neuroscience and Neuroengineering Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China

    Ping Han & Guoyuan Yang

  3. Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Guoyuan Yang

  4. Department of Neurosurgery, Luwan Branch of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Qingfang Sun

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  1. Zhengxing Xie
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  3. Zhenwen Cui
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  4. Baofeng Wang
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Correspondence to Liuguan Bian.

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Xie, Z., Han, P., Cui, Z. et al. Pretreatment of Mouse Neural Stem Cells with Carbon Monoxide-Releasing Molecule-2 Interferes with NF-κB p65 Signaling and Suppresses Iron Overload-Induced Apoptosis. Cell Mol Neurobiol 36, 1343–1351 (2016). https://doi.org/10.1007/s10571-016-0333-8

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