Human Dental Pulp Stem Cell Secretome Restores Ischemic Stroke–Impaired Motor and Cognitive Functions by Reprogramming Redox and Inflammatory Signaling

ABSTRACT Ischemic stroke induces oxidative stress, neuroinflammation, neuronal death, and synaptic dysfunction, leading to persistent motor and cognitive deficits. The human dental pulp stem cell (hDPSC) secretome is a promising cell‐free therapeutic candidate containing neurotrophic, antioxidant, and immunomodulatory factors. Here, we investigated its therapeutic effects in a photothrombotic mouse model of ischemic stroke and CoCl 2 ‐induced hypoxic BV2 microglial cells. Proteomic profiling identified antioxidant‐associated proteins, including SOD2, GSR, and GSTP1, and microglial phenotype‐related candidates, including GRN, CSF1, and LRP1. hDPSC secretome treatment reduced stroke‐induced infarct volume and attenuated stroke‐increased neuronal apoptosis, neuronal ROS accumulation, and NF‐κB‐associated inflammatory signaling in the cortex and hippocampus. It also shifted microglial marker expression toward an M2‐associated profile and improved stroke‐impaired hippocampal neurogenesis, vascular remodeling, and synaptic organization. Proteomic analyses further identified coordinated changes in pathways related to oxidative phosphorylation, inflammatory responses, calcium signaling, SNARE‐associated vesicular transport, and ROBO–Rho‐associated cytoskeletal remodeling. These molecular and cellular changes were associated with improved motor coordination, spatial learning and memory, contextual memory, and anxiety‐like behavior. These findings support the hDPSC secretome as a cell‐free therapeutic candidate for post‐stroke functional recovery linked to redox, inflammatory, neurovascular, and synaptic remodeling.