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

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.

Ferrimagnetic Nanochains‐Based Mesenchymal Stem Cell Engineering for Highly Efficient Post‐Stroke Recovery

“…Administration of adenovirus‐transfected BDNF‐overexpressing MSCs through intracerebral transplantation or intranasal delivery9b has been demonstrated to reduce neurological deficits after cerebral ischemia. More recently, lentivirus‐transfected MSCs also showed the potential to treat cerebral ischemia through a less invasive venous approach . However, to the best of our knowledge, non‐viral system, that can successfully engineer MSCs for efficient therapy post‐ischemic stroke via intravenous administration, has never been reported yet.…”

“…BDNF has been proved as one of the essential neurotrophic factors that is beneficial for post‐ischemic stroke recovery, due to its critical role in neuroprotection and neurogenesis, as well as angiogenesis . Currently, genetic manipulation of MSCs using virus is the main strategy to gain hypersecretion of BDNF 9b,10. However, viral‐based genetic engineering is presently restricted due to their safety concerns .…”

Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy

“…Although all four analytes fall into the category of mainly pro‐inflammatory effectors, some studies have provided evidence of their pleotropic, antiinflammatory, and neuroprotective roles. IL‐6 is suggested to have antiinflammatory properties with enhancing neurogenesis abilities in the CNS While IL‐8 and VEGF are potent angiogenic factors with a recently investigated neuroprotective effect, some evidence has also supported the neuromodulatory effects of MCP‐1 in the CNS . Despite this similar trend, the concentration of the top analytes produced varied greatly between patients.…”

Bone marrow mesenchymal stem cells stimulated with low‐intensity pulsed ultrasound: Better choice of transplantation treatment for spinal cord injury

“…BMSCs transplantation therapy is promising in mitigating the extent of SCI, not only due to a favorable ethical profile and safety, but also due to providing beneficial effects on various postinjury aspects: inflammation, apoptosis, axonal regrowth, angiogenesis, tissue sparing, astroglial scar, and motor recovery . It is well known that BMSCs secrete a large variety of molecules and many studies have shown beneficial impacts from these factors such as brain‐derived neurotrophic factor (BDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin‐like growth factor (IGF), epidermal growth factor (EGF), and more …”

“…[9][10][11][12] It is well known that BMSCs secrete a large variety of molecules and many studies have shown beneficial impacts from these factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), and more. [13][14][15][16][17][18][19] Previously, neurotrophin and physical stimulation were commonly employed to enhance the effect of BMSCs. Specifically, low-intensity pulsed ultrasound (LIPUS), as a physical stimulation, appeared to be an effective assistant method.…”