Endogenous neural progenitor cells in the repair of the injured spinal cord

Stem cell treatments, and in particular, stem cell transplants have been identified as potential therapeutic strategies for a range of neurodegenerative and acquired conditions of the central nervous system (CNS). Stem cell transplants are seen as a way of replacing lost neurons, or providing a cellular environment that is more permissible for axon and cell regeneration. An alternate strategy to transplantation of exogenous stem cells is the recruitment and manipulation of endogenous neural progenitor cells (NPC). NPCs exist in the spinal cord and have been shown to proliferate, migrate and differentiate in response to injury (Mothe and Tator, 2005; Meletis et al., 2008; Hamilton et al., 2009). NPCs may have a wider role than previously thought and it has been reported that NPCs also engage in ‘cross talk’ with immune cells and may be able to modulate the inflammatory response following injury. Our research has focussed on determining the exact timing and location of NPC activation after injury. It is clear that there will be a critical window of opportunity to implement a treatment that harnesses the NPC response to spinal cord injury (SCI), and that this must occur before the full cascade of inflammation has been initiated. Traumatic SCI causes the destruction of neuronal and glial cells leading to the disruption of sensory and/or motor functions. To date, there is no known cure for SCI. There is evidence that primitive vertebrates such as the teleost fish (Zupanc and Sîrbulescu, 2012) and lizards (Fisher et al., 2012) are able to regenerate spinal tissue after trauma resulting in extensive axonal regrowth and functional recovery. In these animals it is the recruitment of NPCs that plays a major role in the regeneration. NPCs are the precursor to all of the neural cells neurons, astrocytes and oligodendrocytes. Following injury, including axonomy, in the lower vertebrates several genes and structural proteins such as Sox1 and fibroblast growth factor-2 are upregulated (Ferretti et al., 2001) which drives the regeneration of neuronal cells and eventually leads to an elongation and regrowth of the spinal cord. Vertebrate mammals have lost this capacity to regrow nervous tissue following injury even though NPCs are found lining of the central canal of the spinal cord. During non-pathological conditions, they remain in a quiescent state in the ependymal layer and demonstrate minimal proliferation activity to maintain the homeostasis of neural cells in the spinal cord (Hamilton et al., 2009). In rodent models NPCs are observed to increase proliferation and differentiation significantly and then migrate to the lesion area following a SCI (Mothe and Tator, 2005; Meletis et al., 2008). However, in rodent models, migrating NPCs are more likely to differentiate into astrocytes forming the glial scar (Mothe and Tator, 2005). While differentiation into all three lineages can occur in vitro under the correct growth conditions, no spontaneous differentiation of NPCs into neurons in vivo has been documented. One study by Guo et al. (2014) induced the transcription factor Sox11 via a lentiviral vector in a mouse SCI model, and demonstrated that it is possible to differentiate NPCs into neurons in vivo. In ependymal cells, the activation of Sox11 is associated with an upregulation of Nestin, a type VI intermediate filament protein found predominately in NPCs in the developing or injured spinal cord (Tzeng, 2002). Consequently these cells have the potential to be manipulated in situ, offering a novel approach to restore the injured spinal cord and much effort is made to identify the response of NPCs to traumatic SCI in relation to location, time and inflammation.