The spinal cord undergoes diffuse swelling and the central grey matter shows signs of petechial haemorrhage

Cell necrosis and the activation of local astrocytes and microglia are also observed immediately after the injury

Subsequent secondary events include free radical production, ionic (e.g. Ca++) deregulation and glutamate excitotoxicity (immediate — hours); changes in the blood–brain barrier (BBB) permeability, activation of a multifaceted inflammatory response that involves soluble inflammatory mediators and a variety of cells such as astrocytes, microglia, T cells, neutrophils and cord-infiltrating monocytes, oligodendrocyte apoptotic cell death and demyelination, (acute —days); astroglial proliferation and formation of a gliotic scar that interferes with axonal sprouting (intermediate — weeks to months); and retrograde Wallerian axonal degeneration, dynamic maturation of the lesion up to the development of cysts and/or syrinxes, and delayed neuronal dysfunctionand neuropathic pain (chronic – several months)

Virtually all therapies that have shown promise at the preclinical stage of study have failed to translate into clinically effective treatments

For this reason, the potential of NPC transplantation to drive spinal cord repair has been widely investigated, as NPCs may provide an effective treatment by either directly replacing those cells lost owing to the injury (e.g. oligodendrocytes), influencing/ modifying the environment in a way that supports axonal regeneration, providing neuroprotection, or re-setting the inflammatory response to a mode that heals the damaged tissue

Adult mammalian NPCs from different sources have been transplanted into a wide range of SCI models with significant clinical improvement

Most of the studies have delivered NPCs focally to increase their viability at the injury site

While evidence exists in support of an astroglial differentiation default mode shown by transplanted embryonic NPCs in both the developing and the adult cord, some pioneering work suggests that NPCs survive, migrate and generate functional remyelinating oligodendrocytes, which promote functional recovery when transplanted sub- acutely (namely 2 weeks) – but not chronically (namely 8 weeks) – after SCI

However, other approaches have more convincingly established that the transplantation of somatic NPCs in experimental SCI yields a generally low degree of survival – as the injury creates a highly toxic environment – and differentiation most of which was biased towards a glial fate (Bottai et al., 2008) thus challenging the initial expectation of achieving predominant neuronal/oligodendroglial cell replacement in vivo (Cao et al. 2001)

There is also a growing belief that the severity (and type) of the injury, as well as the time after injury at which cells are transplanted, are two major key factors influencing the capability of grafted NPCs to affect the healing of the damaged spinal cord tissue

As such, rat spinal cord-derived somatic NPCs failed to induce any detectable functional recovery when transplanted hyperacutely at the level of injury in a severe (35-g) clip-induced SCI model (Parr et al., 2007), but were indeed significantly efficacious when transplanted as early as 9 days after injury in a milder (27-g) model of SCI (Parr et al., 2008)

Furthermore, the homogeneity vs. heterogeneity of the neural stem/progenitor cell preparation is a key point

As such, prominent neuronal differentiation is reliably achieved with primary foetal tissue and when glially and neuronally restricted progenitors are combined, but not when only neuronally restricted progenitors are grafted to the injured spinal cord

Strategies to overcome the observed poor survival and differentiation potential of transplanted NPCs have included combination with valproic acid or neurotrophic growth factors, which promoted neuronal differentiation and established functional synapses between host axons and graft neurons at the injury site

The use of engineered NPCs transduced with transcription factors or survival genes (Hwang et al., 2009; Lee et al., 2009), as well as the co-transplantation with ‘scaffold’ cells such as mesenchymal/stromal stem cells or olfactory ensheathing cells (Oh et al., 2010; Wang et al., 2010), has increased the survival, migration and differentiation of transplanted NPCs and the final functional recovery observed