MiR-138 reprograms dental pulp stem cells into GABAergic neurons via the GATAD2B/MTA3/WNTs axis for stroke treatment

Prolonged periods of ischemia and hypoxia pose significant challenges to exogenous stem cell transplantation, including minimal cell survival, varied differentiation, and poor integration with existing neural networks. Dental pulp stem cells (DPSCs) are an important choice for stem cell treatment for their excellent potential of neural differentiation and easy accessibility. Stable overexpression of miR-138 in DPSCs were injected into MCAO model mice via brain stereotaxic localization to explore the therapeutic effect on stroke and the related mechanisms by trans-synaptic viral tracing, immunostaining, bioinformatics analysis, behavioral tests and electrophysiological assays. DPSCs transfected with miR-138 can treat stroke by reducing neuroinflammation, decreasing neuronal apoptosis, and promoting neural regeneration, resulting in structural and functional repair of post-stroke neural networks. Among them, miR-138 can regenerate nerves because it can break down GATA zinc finger domain-containing protein 2B (GATAD2B), disrupt nucleosome remodeling complex (NuRD), and transfer MTA from nucleus to cytoplasm. The MTA3 was then transferred from the nucleus to the cytoplasm, activating the Wnt signaling pathway, which finally led to the differentiation of DPSCs into GABAergic neurons and the repair of neuronal death caused by stroke. Within this study, we introduce a novel DPSCs reprogramming approach designed to enhance the differentiation of GABAergic neurons and bolster their viability within the ischemic stroke context, and delineate the regulatory mechanism involving miR-138, which initiates GABAergic neuronal differentiation via modulation of the GATAD2B/MTA3/WNTs signaling pathway.