When cells (including SCs) of the rat PNS could be purified and expanded in number in tissue culture, Richard Bunge in 1975 envisioned that SCs could be introduced to repair the CNS. SCs are important candidates for spinal cord repair. They are known to be essential for regeneration of PNS axons following injury. They produce growth factors and extracellular matrix components important for axon growth and can myelinate axons in the CNS, restoring electrical activity. They can be prepared in large numbers in culture and, importantly, could be autologously transplanted into spinal cord injured persons after acquiring SCs from one of their peripheral nerves. SCs can be genetically engineered to produce factors to promote repair. Up to 10 million SCs may be obtained from a human adult sural nerve biopsy; these can be expanded to 100 million in 3 to 5 weeks. In 1980, a key study was reported by the Aguayo team showing that, when a piece of peripheral nerve was inserted into a complete gap in the spinal cord, axons regenerated into the implant. Thus, we decided to test the efficacy of transplanting purified populations of SCs. When a bridge of rat SCs was introduced into a complete transection gap in the spinal cord, Xu et al (1997) found that axons grew into the SC bridge from both spinal cord stumps. There were 2,000 SC-myelinated axons and eight times more non-myelinated axons in these bridges. A spinal cord injury (SCI) contusion model revealed that the transplanted SCs reduced cyst formation, protected spinal cord tissue from secondary damage, and supported axon growth into the SC implant in which 5,000 SC-myelinated axons were present after some weeks. Strategies combining SC transplantation with methylprednisolone, neutrophins, olfactory ensheathing cells, elevation of cyclic AMP or chondroitinaso all led to increased repair and function. There were more myelinated axons in implants, more regenerated axons from neurons above the spinal cord, some exit of regenerated axons from the graft into the caudal spinal cord and improvement in hindlimb movement. When a neurotrophin mimicking the actions of brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was generated by SCs following insertion of the DNA for D15-A, there was a 5-fold increase in graft volume and SC number and an increase in SC-myelinated axons from 5,000 to 26,000 (Golden et al., 2007). If D15-A was further modified to reduce its affinity to p75 NTR, after SCI SC survival was increased 10X and SC-myelinated axons were 6X more numerous (Enomoto et al 2013). Brainstem axons were increased in the graft. Kanno et al (2014) combined SCs with D15-A and/or chondroitinase. Animals receiving the full combination exhibited better outcomes than with either the growth factor or the enzyme. The transplants contained 10,000 more SC-myelinated axons. The borders of SC implants were better interdigitated with the host cord with chondoitinase. More neurons above the spinal cord responded to the full treatment. Walking scores were improved and there was lessened pain in the hindlimbs. Other work has pointed to the importance of the state of astrocytes following injury. If the border between the SC implant and the spinal cord is sharp, there is little extension of axons into the implant. In contrast, when the interface border is irregular due to extension of astrocyte processes into the SC implant, axons regenerate into the implant; the higher the number of astrocyte processes in the implant, the more axons regenerated into the implant. Electro microscopy revealed that in the SC bridge there are tunnel-like structures containing astrocytes, SCs and axons, all encircled by basal lamina. Studies by Guest et al (1997), demonstrated that human SCs are as robust as rat SCs in promoting axon regeneration into the SC bridge and myelination of the regenerated axons. Various types of axons were present in the bridge and some spinal and sensory axons were observed to leave the bridge and enter the spinal cord. Interestingly, interdigitated interfaces were observed, in agreement with our rat studies. Pre-clinical data from transplantation studies with rat and human SCs in multiple species, rats, pigs and primates, supported the feasibility of transplanting SCs into humans for spinal cord repair. These data contributed to obtaining approval from the FDA in July 2012 for an open label, unblinded, non-randomized, and non-placebo dose escalation clinical trial to assess safety of autologous human SC transplantation.