Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia

Lili Zhou,Qingming Lin,Zhiqun Tan,Lan Yao,Peng Wang,Kahong Leong,Zitong Huang

doi:10.1038/cddis.2017.184

Abstract

Cardiac arrest-induced global cerebral ischemia injury (CA-GCII) usually leads to a poor neurological outcome without an effective treatment. Bone marrow-derived mesenchymal stem cells (BMMSCs) may provide a potential cell-based therapy against neurologic disorders through induction of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). To optimize the neuroprotective efficacy of BMMSCs further, in this study we have derived BMMSCs, which co-overexpress both BDNF and VEGF, and tested them for the treatment of CA-GCII in a rat model. Lentiviruses that express rat BDNF exon IV or VEGF-A were created using the bicistronic shuttle vectors of pLVX-IRES-ZsGreen1 and pLVX-IRES-tdTomato, respectively. BMMSCs that were co-transduced with the engineered lentiviruses with co-overexpression of both BDNF and VEGF along with corresponding fluorescent protein reporters were injected via jugular vein of rats that just recovered from a cardiac arrest. Animals were then scored for neurofunctional deficits and examined for brain pathology and gene expression relevant to the engraftment seven days after the treatments. We demonstrate that anchorage of lentiviral vector-transduced BMMSCs, which co-overexpressed both BDNF and VEGF in the hippocampus and temporal cortex along with significantly ameliorated brain pathology and improved neurofunctional performance in CA-GCII rats after transplantation. These findings provide a proof of concept for the further validation of engineered BMMSCs for the treatment of CA-GCII patients in clinical practice in the future.

Highlights

Cardiac arrest (CA) is associated with both high morbidity and mortality rates and poses the most serious threat to human life.[1]
brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) expression in the brain of CA-induced global cerebral ischemic injury (CA-GCII) rats after transplantation of bone marrow-derived mesenchymal stem cells (BMMSCs). The abundance of both BDNF and VEGF is relatively low in the rat brain, increased expression of these two factors was found in the hippocampus and temporal cortex after restoration of spontaneous circulation (ROSC).[16,17]
Despite a high proportion of pulmonary retention,[24] certain number of BMMSCs administered intravenously still successfully migrated into lesioned zones of the brain with CA-GCII, in the hippocampus and cortex.10,21Accordingly, here we employed BMMSCs with lentivirus-directed co-overexpression of BDNF and VEGF to optimize the therapeutic benefits by delivering the engineered cells to the rat brain via the jugular vein injection after ROSC from CA-GCII

Summary

Introduction

Cardiac arrest (CA) is associated with both high morbidity and mortality rates and poses the most serious threat to human life.[1] In recent years, with the continuous improvement in the emergency network and broad application of cardiopulmonary resuscitation and defibrillation technology, there is an increase in the success rate of resuscitation of out-of-hospital CA patients with restoration of spontaneous circulation (ROSC).[2] Many of these patients usually suffer from complicated neural dysfunction or even death as a sequel to brain damage due to global cerebral ischemia following CA.[3] Despite the use of neuroprotective medicines and hypothermic treatments, which to some extent may ameliorate brain injury in clinic,[4] there is still an urgent demand for new treatments to improve the prognosis of CA-induced brain injury. The results indicate markedly enhanced neuroprotective potency of BMMSCs for CA-induced global cerebral ischemia

Methods

Results

Conclusion