Glial cells are the most abundant cells in the nervous system. They are closely associated with neurons and were previously described simply as supportive nervous tissue. A deeper understanding of glial cell biology, however, has demonstrated that glial cells exhibit a multitude of complex roles and are essential for the development and function of the entire nervous system (Jessen 2006). Glial cells are a heterogeneous population of cells that differ in developmental origin, molecular composition, structure and specific behaviour, and exist together with neurons and other cells in an integrated and co-dependent system (Chung and Barres 2012). Throughout the nervous system, glial cells have crucial roles in axonal extension and guidance, protection against mechanical, chemical and oxidative injury, as well as preservation of the electrical and chemical balance of all neurons (Ndubaku and de Bellard 2008).

Glial cells can be broadly classified as being either central nervous system glia or peripheral nervous system glia. In the mature central nervous system (CNS), there are two major types of glial cells of neural origin; astrocytes and oligodendrocytes. Other types of CNS glial cells exist that originate from non-neuronal precursors; microglia constitute part of the innate immune system and originate from macrophage lineages (Chugani et al. 1991). In the peripheral nervous system (PNS), Schwann cells constitute the main glial cell type, with the exception of the olfactory nervous system, which is populated by specialized glia termed olfactory ensheathing cells (OECs).

Astrocytes play a critical role in the function and homeostasis of the CNS. They are required for the formation and maintenance of the blood-brain barrier, provide support for axonal extension and play an active role in neuronal signalling by exchange of ions and production of neurotransmitters, as well as cell adhesion and synapse signalling molecules (Kriegstein and Gotz 2003). Astrocyte–neuron interactions are known to secure the survival and normal function of neurons (Jessen 2004). Numerous studies have demonstrated that astrocytes play important neuroprotective roles, in neurodegenerative disorders (reviewed by Singh et al. 2011; Cabezas et al. 2012) and they have the ability to promote neuronal survival by protecting against reactive oxygen species and other stressors (Lopez et al. 2007).

After spinal cord injury, astrocytes respond rapidly by migrating to the injury site, where they proliferate and form a compact structure, a glial scar, to preserve the blood-brain barrier, protecting the CNS and maintaining the adequate ionic environment necessary for nerve function. However, the glial scar eventually becomes a physical barrier that stops damaged axons from regenerating and reconnecting (Fig. 13.1) (Leal-Filho 2011). Furthermore, astrocytes respond to neuronal injury by increasing their proliferation and by secreting glycoproteins such as chondroitin sulfate proteoglycans (CSPG), which act to inhibit axon elongation (Table 13.1) (Qiu et al. 2002; Su et al. 2009).

Oligodendrocytes are morphologically similar to astrocytes, albeit with fewer and smaller branched processes. They play different roles in the modulation of neuronal function as well as the regulation of proliferation , survival and differentiation of neurons (Jauregui-Huerta et al. 2010) The most important role of oligodendrocytes, however, is to myelinate axons. The myelin sheet provides electrical insulation around the nerve fibres, speeding the transmission of electrical signals (Jessen 2004). The myelin layer also protects the axons by creating a “safe chamber”, resembling a growth-promoting channel through which the axon extends. After spinal cord injury, populations of oligodendrocytes are rapidly affected by high levels of glutamate and massive cell death follows. Oligodendrocytes that do survive produce neurite outgrowth inhibitor (Nogo), myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp) (Table 13.1), proteins that bind to the Nogo receptor, repressing myelin production and affecting axonal outgrowth and neuronal synapses (Jones et al. 2003). Microglia, which are essentially macrophages present within the CNS, respond to injury by migrating to the injury site, where they phagocytose debris, secrete a range of both pro- and anti-inflammatory cytokines and growth factors which initially have a neuroprotective effect. Over time, however, microglia near and in the injury site respond to the constant prolonged activation by secreting molecules that are growth-inhibitory or toxic, thus repressing axonal regeneration (Chatzipanteli et al. 2002; Pearse et al. 2003; Block and Hong 2005). The majority of the activated microglia transition to the M1 type, which can directly induce neuronal death (Kigerl et al. 2009; Gao et al. 2013). Thus, together with the glial scar, the local environment at a CNS injury site inhibits long-term neuronal extension and regeneration.

The PNS differs dramatically from the CNS in terms of capability to regenerate itself after injury. In contrast to central nerves, peripheral neurons in general regenerate after injury, unless large nerves have been completely severed. Schwann cells play an active role in repair of peripheral damaged nerves as a consequence of their ability to differentiate, migrate, proliferate, secrete growth factors , and produce myelin. Schwann cells are classified as either myelinating or non-myelinating. Myelinating Schwann cells enwrap individual peripheral axons, forming the myelin sheath, whereas the non-myelinating type have metabolic and mechanical support functions (Jessen 2004). After spinal cord injury, Schwann cells migrate from the periphery into the injury site within in the CNS, and participate in endogenous repair processes (Table 13.1). They re-enter the cell cycle, lose their myelinating phenotype and de-differentiate into an immature state, and begin to express trophic factors and cell adhesion molecules that provide a more favourable environment for axon regeneration and extension (Oudega and Xu 2006).

One approach to improve the outcomes after spinal cord injury is to transplant glial cells into the injury site to reduce inflammation , and which will help form a glial bridge across the injury site and thereby promote axon extension. The glial of the PNS system, Schwann cells and OECs, have been trialled in animal models and in humans with various outcomes. The OECs have unique characteristics that may confer an advantage over other glial cell types for transplant therapies.

The mammalian olfactory nervous system is one of the few regions in the CNS in which neurogenesis continuously occurs during the lifetime of the organism (Mackay-Sim and Kittel 1991a, b). The primary sensory neurons of the olfactory system line the dorsal/caudal nasal epithelium and are directly exposed to the environment (Fig. 13.2). The neurons are subjected to attack and destruction by bacterial (St John et al. 2014) and viral pathogens as well as toxins within the air and thus need to be replaced throughout life. Whilst the average life-span of olfactory neurons has not been clearly determined in humans, mouse olfactory neurons generally live for one to three months. Neurons that degenerate are rapidly replaced by new neurons arising from progenitor cells that line in the basal layer of the olfactory mucosa (Mackay-Sim and Kittel 1991b), a process that occurs throughout life (Ramon-Cueto and Santos-Benito 2001).

The primary olfactory system comprises the olfactory mucosa and the bundles of olfactory nerves that project into the olfactory bulb. Stem cells that line basal layer of the olfactory epithelium give rise to the primary olfactory sensory neurons which migrate apically to populate the olfactory epithelium (Fig. 13.2). Olfactory sensory neurons have a bipolar morphology with a single dendrite extending onto the surface of the epithelium and a single axon projecting to and terminating in the olfactory bulb. Each olfactory neuron expresses a single odorant receptor type with the neurons mosaically distributed throughout the epithelium, but the axons of the same odorant receptor type converge to the same targets within the olfactory bulb (Vassar et al. 1994; Mombaerts et al. 1996). To reach their targets in the olfactory bulb, the axons of the olfactory sensory neurons project through the lamina propria that underlies the olfactory epithelium and pass through the bony cribriform plate to enter the nerve fibre layer which is the outer layer of the olfactory bulb and within the CNS. Thus, new axons must constantly traverse the PNS-CNS border and find their correct targets inside the olfactory bulb (Valverde et al. 1992; Tennent and Chuah 1996; Chehrehasa et al. 2010). The constant ability of olfactory neurons to regenerate and the unique ability of olfactory axons to extend across the PNS-CNS boundary are attributed to the presence of the glia of the olfactory system, called OECs.

Re-establishment of nerve connections after spinal cord injury depends of the ability of axons to extend along a pathway to reach their targets. This living pathway consists of glial cells, which provide a dynamic channel through which axons can extend towards their targets (Ramer et al. 2004; Li et al. 2012). After spinal cord injury, the severed nerves are able to survive and sprout locally. However, they are unable to elongate and re-establish the connections, primarily because the glial pathway is altered, blocked and sometimes completely lost. Consequently, a primary objective in the treatment of spinal cord injury is re-establishment of the glial pathway. Transplantation of glial cells into the injury site is therefore a promising therapeutic approach for repair spinal cord injury (Oudega and Xu 2006).

Glial cell transplantation addresses many of the challenges that must be overcome for successful functional improvement, including (1) re-establishment of a growth-promoting environment, (2) replacement of lost cell populations (neurons and glia) , and (3) facilitation and promotion of axonal regeneration and extension. Pioneering studies have established that transplantation of glial cells can improve axonal repair, enhance re-growth of damaged nerve cells and improve functional recovery (Yan et al. 2001; Santos-Benito and Ramon-Cueto 2003). Additionally, glial cells have the potential to produce neurotrophic molecules that activate axon regeneration and extension (Jones et al. 2003; Feron et al. 2005).

Different types of glial cells have been investigated as treatment for spinal cord injury including Schwann cells from peripheral nerves and OECs. Schwann cells have been trialled for transplantation due to the important role they play in axon regeneration and myelination. Schwann cells transplanted to the damaged spinal cord can stimulate regeneration of damaged neurons, presumably due to the production of neurotrophic factors (Park et al. 2010), and can also enhance axon remyelination and extension (Lavdas et al. 2010; Flora et al. 2013). However, the axonal regeneration has thus far been limited to restricted areas because Schwann cells have failed to migrate considerable distances into the injured tissue (Lankford et al. 2008). The limited migration is most likely due to unfavorable interaction between the transplanted Schwann cells and host astrocytes (Li et al. 2012). Additionally, Schwann cells have been reported to inhibit myelination by the secretion of connective tissue growth factor, whereas OECs do not (Lamond and Barnett 2013). Thus, Schwann cells may not be the optimal cell type for transplantation therapies due to their poor migration properties, inability to freely interact with endogenous glia and expression of inhibitory molecules.