Intravenous administration of DPSCs and BDNF improves neurological performance in rats with focal cerebral ischemia

Abstract

Dental pulp stem cells (DPSCs) are considered as an ideal stem cell source for the treatment of neurological diseases. In this study, we evaluated the therapeutic potency of DPSCs and brain-derived neurotrophic factor (BDNF) in focal cerebral ischemia using animal models. Following middle cerebral artery occlusion (MCAO), rats were randomized into four groups: the BDNF, DPSCs, DPSCs+BDNF and the controls injected with saline. DPSCs were transplanted and BDNF was injected into the DPSCs+BDNF group via the tail vein. The fate of the transplanted DPSCs in rat brains was evaluated using immunofluorescence, immunohistochemistry, western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Adhesive removal tests and the modified neurological severity scores were used to estimate the restoration of neurological function. Proliferation of intravenously transplanted DPSCs was observed in the peripheral ischemic regions of the MCAO models. A green fluorescent dye PKH67 was used to label cells. PKH67-labeled DPSCs were co-localized with neuronal cell markers and 4′,6-diamidino-2-phenylindole (DAPI). DPSC transplantation combined with BDNF induced the expression of neural differentiation markers such as nestin, doublecortin (DCX) and neuronal specific filament (NF-H), suggesting that BDNF enhances the survival of DPSCs and differentiation into neuronal cells. Treatment with DPSCs combined with BDNF promoted the recovery of neurological function more effectively compared with BDNF injection or DPSC transplantation alone. In conclusion, treatment with DPSCs combined with BDNF enhances neurological recovery after stroke suggesting a novel therapeutic strategy against cerebral ischemia.

Alpinia oxyphylla Miq. and Its Active Compound P-Coumaric Acid Promote Brain-Derived Neurotrophic Factor Signaling for Inducing Hippocampal Neurogenesis and Improving Post-cerebral Ischemic Spatial Cognitive Functions

“…Adenoviral transduction of BDNF gene in human bone marrow–derived mesenchymal stem cells (MSCs) efficiently promotes its survival after transplantation, enhances the proliferation of endogenous NSCs, and promotes functional recovery in a middle cerebral artery occlusion (MCAO) rat model ( Jeong et al, 2014 ). BDNF increases the survival and differentiation of dental pulp stem cells (DPSCs) and promotes the recovery of neurological functions in a cerebral ischemia animal model with DPSC transplantation ( Zhang X. et al, 2018 ). In addition, plasma BDNF level is used as a biomarker to reflect cell viability and functional recovery in the transplantation of MSCs ( Nakamura et al, 2019 ).…”

Dental Pulp Stem Cells: An Attractive Alternative for Cell Therapy in Ischemic Stroke

“…To date, there are several preclinical studies demonstrating that DPSCs exert neuroprotective effect resulting in improved functional outcome and reduced infract volumes in rodent stroke models (Table 3) (52, 66, 68, 70–76). No obvious deleterious effects were observed in these studies (66, 68, 71–73, 75), but have not been always explicitly looked for.…”

Recent Advances in Cell-Based Therapies for Ischemic Stroke

“…The immunosuppressive properties of DPSCs make them attractive for use in allogeneic transplantation. The neurotrophic factors secreted by DPSCs are involved in processes mediated by nerve growth factor (NGF), neurotrophin-3, brain-derived neurotrophic factor (BDNF), glial cell-derived neurotropic factor (GDNF), and vascular endothelial growth factor (VEGF); these molecules promote neuronal survival, cellular proliferation, differentiation, and migration [55]. DPSCs exhibit properties of both neural stem cells and mesenchymal stem cells (MSCs), with reported utility for the treatment of cerebral ischemia [56][57][58].…”