Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice

Background: Hypoxic-ischemic (HI) encephalopathy causes mortality and severe morbidity in neonates. Treatments with a therapeutic window >6 h are currently not available. Here, we explored whether delayed transplantation of allogenic neural stem cells (NSCs) at 10 d after HI could be a tool to repair HI brain injury and improve behavioral impairments. Methods: HI was induced in 9-d-old mice. Animals received NSCs or vehicle intracranially in the hippocampus at 10 d post-HI. Sensorimotor performance was assessed by cylinder rearing test. Lesion size, synaptic integrity, and fate of injected NSCs were determined by immuno-stainings. Neuroinflammation was studied by immuno-stainings of brain sections, primary glial cultures, and TNFα ELISA. Results: NSC transplantation at 10 d post-insult induced long-term improvement of motor performance and synaptic integrity, and reduced lesion size compared to vehicle-treatment. HI-induced neuroinflammation was reduced after NSC treatment, at least partially by factors secreted by NSCs. Injected NSCs migrated toward and localized at the damaged hippocampus. Transplanted NSCs differentiated toward the neuronal lineage and formed a niche with endogenous precursors. Conclusion: Our study provides evidence of the efficacy of NSC transplantation late after HI as a tool to reduce neonatal HI brain injury through regeneration of the lesion.