Abstract
Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback.
Highlights
These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord
In caudal spinal neurodevelopment, neural progenitors are derived from transient neuro-mesodermal progenitors that are capable of generating both spinal cord neural and mesodermal progenitors [94]. This principle of spinal cord development can be used to derive spinal cord neural stem cells from human pluripotent stem cells. When these homotypic embryonic stem cells (ESCs)- or induced pluripotent stem cells (iPSCs)-derived neural stem/progenitor cells are successfully transplanted into the injured spinal cord, they differentiate into both neurons and glia, extend a large number of axons into the surrounding spinal cord and attract host axon regeneration into the graft [71,93]
This is significant, because previous studies have shown that rat neural progenitor cell (NPC) grafts of spinal cord identity support regeneration of the corticospinal tract (CST), a motor system most refractory to previous regeneration efforts [69]
Summary
Traumatic spinal cord injury is most commonly caused by compression, laceration and contusions which lead to severe impairment of motor/sensory function below the level of injury [1]. The initial traumatic event that may comprise fractures and/or dislocation of the vertebral column results in disruption of the vasculature, neurogenic shock and alterations in ion and neurotransmitter release. This will set the stage for the secondary phase of injury [4,5,6,7] including post-traumatic ischemia, disbalance of neuronal electrolytes, accumulation of free radicals, glutamate excitotoxicity and inflammatory responses [8,9,10]. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses after the lesion [11,12]. Some cytokines and growth factors secreted by microglia/macrophages can support neuronal survival, oligodendrogenesis, remyelination and angiogenesis [13,14,15,16,17], pro-inflammatory cytokines are detrimental for axonal growth and neuronal survival [18,19,20]
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