Effect of HMGB1 on the Paracrine Action of EPC Promotes Post-Ischemic Neovascularization in Mice

Authors

  • Chao Chen,

    1. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
    2. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Xiaojie Lin,

    1. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Jixian Wang,

    1. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
    2. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Guanghui Tang,

    1. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Zhihao Mu,

    1. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
    2. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Xiaoyan Chen,

    1. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Jin Xu,

    1. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Yongting Wang,

    1. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
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  • Zhijun Zhang,

    Corresponding author
    1. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
    • Correspondence: Guo-Yuan Yang, Ph.D., M.D., Room 213, Education Building 3, 1954 Hua Shan Road, Med-X Research Institute and School of Biomedical Engineering Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China. Telephone: 86-21-62933186; Fax: 86-21-62932302; e-mail: gyyang0626@gmail.com; or Zhijun Zhang, Ph.D., Room 211, Education Building 3, 1954 Hua Shan Road, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China. Telephone: 86-21-62933186; Fax: 86-21-62932302; e-mail: zhangzhij@gmail.com

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  • Guo-Yuan Yang

    Corresponding author
    1. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
    2. Neuroscience and Neuroengineering Center, Med-X Research Institute Shanghai Jiao Tong University, Shanghai, People's Republic of China
    • Correspondence: Guo-Yuan Yang, Ph.D., M.D., Room 213, Education Building 3, 1954 Hua Shan Road, Med-X Research Institute and School of Biomedical Engineering Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China. Telephone: 86-21-62933186; Fax: 86-21-62932302; e-mail: gyyang0626@gmail.com; or Zhijun Zhang, Ph.D., Room 211, Education Building 3, 1954 Hua Shan Road, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China. Telephone: 86-21-62933186; Fax: 86-21-62932302; e-mail: zhangzhij@gmail.com

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Abstract

Transplantation of endothelial progenitor cells (EPCs) leads to better outcomes in experimental stroke, but the mechanism remains unclear. It was reported that astrocytic-high mobility group box1 (HMGB1) promoted endogenous EPC-mediated neurovascular remodeling during stroke recovery. It is unclear whether HMGB1 involves in exogenous EPC-mediated stroke recovery. In this study, we aim to explore whether microglial HMGB1 contributes to human peripheral blood-derived (hPB)-EPCs-mediated neurovascular remodeling by modulating the paracrine function of exogenous hPB-EPCs. Coculturing hPB-EPCs with lipopolysaccharides stimulated BV2 cells upregulated Interleukin-8 expression in hPB-EPCs; this was blocked by treating BV2 cells with HMGB1 inhibitor Glycyrrhizin. Conditioned medium (CM) of hPB-EPCs cocultured with BV2 cells promoted the viability and tube formation of human umbilical cord vein cells. Inhibiting either HMGB1 or IL-8 could block the effect of hPB-EPCs CM. In vivo study showed hPB-EPCs transplantation improved neurobehavioral outcomes, reduced brain atrophy volume, and enhanced neovascularization in transient middle cerebral artery occlusion (tMCAO) mice. Intraperitoneally administration of HMGB1 inhibitor glycyrrhizin blocked the beneficial effect of hPB-EPC transplantation. We did not observe the integration of green fluorescent protein-labeled hPB-EPCs with microvessels in peri-infarct areas at day-14 after tMCAO. In summary, the result suggested that HMGB1 upregulation in postischemic brain could promote exogenous hPB-EPC-mediated stroke recovery by modulating paracrine function of hPB-EPCs. Stem Cells 2014;32:2679–2689

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