There is growing interest in the use of neural precursor cells to treat spinal cord injury (SCI). Despite extensive pre-clinical research, it remains unclear as to which donor neuron phenotypes are available for transplantation, whether the same populations exist across different sources of donor tissue (e.g., developing tissue vs. cultured cells), and whether donor cells retain their phenotype once transplanted into the hostile internal milieu of the injured adult spinal cord. In addition, while functional improvements have been reported after neural precursor transplantation post-SCI, the extent of recovery is limited and variable. The present work begins to address these issues by harnessing ventrally derived excitatory pre-motor V2a spinal interneurons (SpINs) to repair the phrenic motor circuit after cervical SCI. Recent studies have demonstrated that Chx10-positive V2a SpINs contribute to anatomical plasticity within the phrenic circuitry after cervical SCI, thus identifying them as a therapeutic candidate. Building upon this discovery, the present work tests the hypothesis that transplantation of neural progenitor cells (NPCs) enriched with V2a INs can contribute to neural networks that promote repair and enhance respiratory plasticity after cervical SCI. Cultured NPCs (neuronal and glial restricted progenitor cells) isolated from E13.5 Green fluorescent protein rats were aggregated with TdTomato-mouse embryonic stem cell-derived V2a INs in vitro, then transplanted into the injured cervical (C3-4) spinal cord. Donor cells survive, differentiate and integrate with the host spinal cord. Functional diaphragm electromyography indicated recovery 1 month following treatment in transplant recipients. Animals that received donor cells enriched with V2a INs showed significantly greater functional improvement than animals that received NPCs alone. The results from this study offer insight into the neuronal phenotypes that might be effective for (re)establishing neuronal circuits in the injured adult central nervous system.

Due to the nature of the biological response to traumatic spinal cord injury, there are very limited therapeutic options available to patients. Recent advances in cell transplantation have demonstrated the therapeutic potential of transplanting supportive cell types following spinal cord injury. In particular, pluripotent stem cell derived neural cells are of interest for the future investigation. Use of pluripotent stem cells as the source allows many cell types to be produced from a population that can be expanded in vitro. In this review, we will discuss the signaling pathways that have been utilized to differentiate spinal neural phenotypes from pluripotent stem cells. Additionally, we will highlight methods that have been developed to direct the differentiation of pluripotent stem cells to specific neural fates. Further refinement and elaboration of these techniques might aid in elucidating the multitude of neuronal subtypes endogenous to the spinal cord, as well as produce further therapeutic options for spinal cord injury recovery.

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