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Recombinant Human Erythropoietin Improves the Neurofunctional Recovery of Rats Following Traumatic Brain Injury via an Increase in Circulating Endothelial Progenitor Cells

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Abstract

Previous studies show that circulating endothelial progenitor cells (EPCs) promote angiogenesis, which is a process associated with improved recovery in animal models of traumatic brain injury (TBI), and that recombinant human erythropoietin (rhEPO) plays a protective role following stroke. Thus, it was hypothesized that rhEPO would enhance recovery following brain injury in a rat model of TBI via an increase in the mobilization of EPCs and, subsequently, in angiogenesis. Flow cytometry assays using CD34- and CD133-specific antibodies were utilized to identify alterations in EPC levels, CD31 and CD34 antibody-stained brain tissue sections were used to quantify angiogenesis, and the Morris water maze (MWM) test and the modified Neurological Severity Score (mNSS) test were used to evaluate behavioral recovery. Compared with saline treatment, treatment with rhEPO significantly increased the number of circulating EPCs on days 1, 4, 7, and 14 (P < 0.05), improved spatial learning ability on days 24 and 25 (P < 0.05), and enhanced memory recovery on day 26 (P < 0.05). Moreover, rhEPO treatment decreased mNSS assessment scores on days 14, 21, and 25 (P < 0.05). There was a strong correlation between levels of circulating EPCs and CD34- and CD31-positive cells within the injured boundary zone (CD34+ r = 0.910, P < 0.01; CD31+ r = 0.894, P < 0.01) and the ipsilateral hippocampus (CD34+ r = 0.841, P < 0.01; CD31+ r = 0.835, P < 0.01). The present data demonstrate that rhEPO treatment improved functional outcomes in rats following TBI via an increase in the mobilization of EPCs and in subsequent angiogenesis.

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Acknowledgments

We thank Li Liu, Weiyun Cui, Fanglian Chen, and Lei Zhang for their excellent technical support. The authors thank Voltaire Gungab for the editorial assistance. This work was supported by grants from the Emerging Project Committee of Science and Technology of Tanggu District of Tianjin (2012XQ15-07), China; the National Natural Science Foundation of China (grants 81100920 and 81200907); and Tianjin Research Program of Application Foundation and Advanced Technology (grants12JCQNJC6800).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurosurgery, Tianjin 5th Center Hospital, Number 41 Zhejiang Road, Tanggu District, Tianjin, 300450, China

    Liang Wang & Zhenlin Liu

  2. Department of Neurosurgery, Nankai Hospital, Number 6, Changjiang Road, Nankai District, Tianjin, 300102, China

    Xiaonan Wang

  3. Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potreto Avenue, Box 1363, San Francisco, CA, 94110, USA

    Hua Su

  4. Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China

    Zhenying Han, Huijie Yu, Dong Wang, Rongcai Jiang & Jianning Zhang

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  1. Liang Wang
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Correspondence to Zhenlin Liu or Jianning Zhang.

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Wang, L., Wang, X., Su, H. et al. Recombinant Human Erythropoietin Improves the Neurofunctional Recovery of Rats Following Traumatic Brain Injury via an Increase in Circulating Endothelial Progenitor Cells. Transl. Stroke Res. 6, 50–59 (2015). https://doi.org/10.1007/s12975-014-0362-x

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  • DOI: https://doi.org/10.1007/s12975-014-0362-x

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