Endothelial Progenitor Cells Transplantation Promotes the Whole Brain Recovery after Focal Ischemic Stroke

Abstract

Background: Ischemic stroke caused severe damages to patients, mostly treatments for ischemic stroke focused recovery on the peri-infarct areas. In this study, we found that focal ischemic stroke caused damages to whole brain, endothelial progenitor cells (EPCs) treatment could significantly promote the recovery of the whole brain after ischemic stroke. Methods: EPCs were infected with lentivirus carrying luc2 and eGFP cassette for bioluminescence imaging (BLI) and labeled with Alkyl-PEI-SPIO for magnetic resonance imaging (MRI). 5×10^5 EPCs were transplanted intracardially 24 hours after photothrombotic ischemic stroke onset. BLI, MRI and behavior test were carried out at different time points. Expression of BDNF, VEGF in the ipsilateral and contralateral hemisphere and infarct volume were analyzed 7 days after EPCs transplantation. Expression of myelin basic protein (MBP) and NeuN in the ipsilateral and contralateral hemisphere were detected 14 days after EPCs transplantation. Findings: EPCs transplantation significantly increased the expression of BDNF, MBP and NeuN in both ipsilateral and contralateral hemisphere, while no significant differences were found in VEGF expression. Also, in vivo MRI results showed that fiber counts and FA values in both ipsilateral and contralateral corpus callosum increased 14 days after EPCs transplantation. No significant differences were found in the infarct volume 7 days after EPCs transplantation. mNSS scores and foot-faults test indicated better functional recovery 14 days after EPCs transplantation. Interpretation: Studies should focus on the whole brain recovery after stroke onset. EPCs treatment offered a powerful therapy method for whole brain recovery after ischemic stroke which may associated with elevated BDNF expression. Funding Statement: This work was supported by the National Key Basic Research Program of China (NOs. 2013CB733800 and 2013CB733803), the National Natural Science Foundation of China (NOs. 81230034 and 81520108015), the National Natural Science Foundation of Jiangsu Province (NO. BK20130057), the National Science Foundation for Youths of China (NOs. 81601544 and 81501522), the Fundamental Research Funds for the Central Universities (NO. 2242018k30004). C. Wang acknowledged the financial support from the China Scholarship Council for his joint PhD scholarship (NO. 201706090204). The funder had no role in the study design, data analysis, write-up or in the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of Interest: The authors have no conflicts of interest to disclose. Ethics Approval Statement: This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Southeast University (approval ID: SYXK-2010.4987). BALB/c nude female mice (8 weeks, 20-23 g, Comparative Medicine Centre of Yangzhou University [SCXK (SU) 2012-0004], Yangzhou, China) were used in this study. Briefly, EPCs were isolated from newborns with all mothers’ informed consent and with the approval of the local hospital ethics committee.