MiR‐199a‐5p enhances neuronal differentiation of neural stem cells and promotes neurogenesis by targeting Cav‐1 after cerebral ischemia

Abstract

AimsMicroRNAs (miRs) are involved in endogenous neurogenesis, enhancing of which has been regarded as a potential therapeutic strategy for ischemic stroke treatment; however, whether miR‐199a‐5p mediates postischemic neurogenesis remains unclear. This study aims to investigate the proneurogenesis effects of miR‐199a‐5p and its possible mechanism after ischemic stroke.MethodsNeural stem cells (NSCs) were transfected using Lipofectamine 3000 reagent, and the differentiation of NSCs was evaluated by immunofluorescence and Western blotting. Dual‐luciferase reporter assay was performed to verify the target gene of miR‐199a‐5p. MiR‐199a‐5p agomir/antagomir were injected intracerebroventricularly. The sensorimotor functions were evaluated by neurobehavioral tests, infarct volume was measured by toluidine blue staining, neurogenesis was detected by immunofluorescence assay, and the protein levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), caveolin‐1 (Cav‐1), vascular endothelial growth factor (VEGF), and brain‐derived neurotrophic factor (BDNF) were measured by Western blotting.ResultsMiR‐199a‐5p mimic enhanced neuronal differentiation and inhibited astrocyte differentiation of NSCs, while a miR‐199a‐5p inhibitor induced the opposite effects, which can be reversed by Cav‐1 siRNA. Cav‐1 was through the dual‐luciferase reporter assay confirmed as a target gene of miR‐199a‐5p. miR‐199a‐5p agomir in rat stroke models manifested multiple benefits, such as improving neurological deficits, reducing infarct volume, promoting neurogenesis, inhibiting Cav‐1, and increasing VEGF and BDNF, which was reversed by the miR‐199a‐5p antagomir.ConclusionMiR‐199a‐5p may target and inhibit Cav‐1 to enhance neurogenesis and thus promote functional recovery after cerebral ischemia. These findings indicate that miR‐199a‐5p is a promising target for the treatment of ischemic stroke.

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“…Furthermore, through the Src kinase and ERK 1/2 signaling pathways, it prevents ischemic cell death in neurons [ 48 , 49 ]. After cerebral ischemia, miR-199a-5p regulates Cav-1 expression, leading to increased expression of BDNF and VEGF, promoting neural stem cell differentiation and endogenous neurogenesis [ 50 ]. Therefore, in neuroinflammatory conditions, TLR4 through the MyD88/NF-κB signaling pathway, regulates the expression of pro-inflammatory factors, leading to increased permeability of the BBB and neuronal cell damage.…”

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