Human induced pluripotent stem cell–derived cortical grafts rebuild motor circuits after brain injury

Traumatic brain injury causes irreversible neuronal loss, and no existing therapy can replace lost cortical tissue and restore its circuitry. We investigated whether human induced pluripotent stem cell-derived cortical organoids could not only repair motor deficits but also reveal how grafted neurons integrate into the adult brain. Cortical organoids were generated via a modified dual-SMAD inhibition protocol and transplanted into the motor cortex of NOD-SCID mice after controlled cortical impact. Mice receiving grafts achieved full recovery of contralateral forelimb motor function within 28 days, while non-transplanted controls showed persistent deficits. Grafts are selectively projected to the canonical efferent motor pathway targets bilaterally, with minimal off-target integration. Strikingly, we identified abundant perinuclear synaptic puncta in host neurons that colocalized with graft-derived axons, human-specific cytoplasmic labeling, and the excitatory synapse marker post-synaptic density protein 95. These structures, present in both local and long-range motor-associated regions, provide the first structural evidence of graft-derived synaptic input directly onto host neuronal cell bodies, suggesting specific organoid cell types are integrating into the host network. Our findings establish that human induced pluripotent stem cell-derived cortical organoids can restore motor function after traumatic brain injury and reveal a cellular integration signature that advances understanding of how transplanted human neurons connect with the injured adult brain.