Neural stem cell (NSC) transplants have been explored as vehicles for promotion of remyelination or neuronal replacement therapy after spinal cord injury.We explored whether NSCs could be utilized to form functional neuronal relays cross the severely injured spinal cord.Previous studies using NSC implants have been limited by modest cell survival when implanted into severe spinal cord injury sites; to address this limitation,we embedded NSCs expressing green fluorescent protein from different species and sources,including rat embryonic spinal cord,human fetal spinal cord,human embryonic stem cells and human induced pluripotent stem cells,into fibrin matrices containing growth factor cocktails,and grafted them to the sites of adult rat completely transected or laterally hemisected spinal cord.Grafted cells differentiated into multiple neural phenotypes,including neurons,which extended large numbers of axons over remarkable distances,including human neurons that extended their axons virtually the entire rostral to caudal rat central nervous system.Notably,axons initially prefer host white matter for long distance growth and were closely contacted with host myelin,contrary to the traditional view of white matter inhibition.Grafted derived axons formed abundant synapses with host cells and some host supraspinal axons regenerated into the NSC graft.Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection,resulting in functional recovery.Thus,properties intrinsic to early stage neurons can mount remarkable axonal growth in the traditional view of the inhibitory milieu of the injured adult spinal cord,resulting in formation of novel relay circuits that signif cantly improve function.