Abstract
Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery.
Highlights
Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements
The findings indicate that upregulation of genes involved in neural precursor maturation, neurite extension, and synapse formation plays a crucial role in graft integration, and that host environment determines the transcriptional profile of implanted cells
Previous investigations on spinal cord (SC)-derived neural stem cells (NSCs) were limited to the application of one single fetal cell line (566RSC)[1,2,7] or to fetal NSCs cultured as neurospheres with the consequent reduction of the neurogenic potential[4,5]
Summary
Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. We describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. The hypothesized benefits of transplantation are diverse, including replacement of lost neurons, creation of a conducive axon growth environment for host axons, production of growth factors, and provision of glial cells to assist function of surviving neurons In order for these mechanisms to occur, graft integration into the host is critical and defining the parameters that regulate its success is fundamental to facilitate translation of cell-based therapies to the clinic. NES cells can be propagated as monolayers for a virtually unlimited number of passages, retain a high and unaltered neurogenic potential over time and preserve the molecular and transcriptional signature of their tissue of origin[17,18]
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