Abstract
Subarachnoid hemorrhage (SAH) is a devastating neurological condition with limited therapeutic options for mitigating secondary brain injury. This study investigates the neuroprotective potential of exosomes derived from human neural stem cells (hNSC-exo) in a rat SAH model, focusing on their molecular mechanisms through single-cell RNA sequencing (scRNA-seq) and transcriptomic profiling. This study demonstrated that hNSC-exo administration significantly ameliorated neurological deficits, reduced blood-brain barrier (BBB) disruption, and attenuated neuronal damage post-SAH. Behavioral assessments revealed improved cognitive and motor recovery in hNSC-exo-treated rats, supported by histopathological evidence of preserved neuronal architecture and reduced edema. scRNA-seq analysis revealed a marked increase in astrocyte proportions and vitality following hNSC-exo treatment, alongside suppression of neurotoxic microglial activation. Transcriptomic profiling identified the BDNF/TRKB signaling pathway as a critical mediator, with hNSC-exo upregulating BDNF and TRKB expression both in vivo and in vitro. Functional validation confirmed that hNSC-exo enhanced astrocyte survival via BDNF/TRKB activation, while knockdown of BDNF or TRKB reversed these protective effects. Furthermore, hNSC-exo mitigated neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-18) and microglial C1q expression. These findings highlight hNSC-exo as a novel therapeutic strategy for SAH, leveraging astrocyte-mediated neuroprotection and BDNF/TRKB pathway activation to counteract secondary injury. This study provides mechanistic insights into exosome-based therapies and underscores their potential for clinical translation in cerebrovascular disorders.