Olfactory ensheathing cells for spinal cord repair: crucial differences between subpopulations of the glia

Abstract

OECs for spinal cord repair: Is repairing the injured spinal cord by olfactory ensheathing cell (OEC) transplantation possible? A recent human trial in which a paralysed man regained some function after transplantation of partially purified OECs suggests that this therapy may be a successful approach (Tabakow et al., 2014). In another human trial in which olfactory mucosa lamina propria was transplanted, patients recovered some motor and sensory function (Wang et al., 2015). While these results show promise, it is clear that improvements are needed to provide patients with increased functional output. Strategies to improve the therapeutic use of OECs may include improving the purification of the OECs used for transplantation, using them in combination with growth factors to combat the inhibitory environment and improve axon growth, the use of nerve bridges, advanced physiotherapy and the use of exoskeleton robotics to reinforce functional connections. Of all these approaches, it is probably crucial that the purity of OECs is primarily addressed to ensure consistency in outcomes. What makes OECs useful for spinal cord repair? OECs are the glia of the peripheral olfactory nerve and provide support to the olfactory sensory neurons. The OECs do not myelinate individual olfactory sensory axons, but instead they wrap up numerous bundles of axons to form the olfactory nerve fascicles. OECs ensheathe the olfactory sensory axons from the base of the olfactory epithelium that lines the olfactory nasal cavity, to the outer layer of the olfactory bulb within the cranial cavity. Perhaps of therapeutic importance, within the outer layer of the olfactory bulb, OECs interact with astrocytes from the central nervous system. Also of potential significance is that during development when the olfactory axons are first projecting out of the olfactory placode that lines the embryonic nasal epithelium, OECs migrate ahead of axons. This has also been demonstrated using live cell in vitro assays in which the motility of OECs directly influenced the movement of the axons (Windus et al., 2011). The olfactory nervous system constantly regenerates throughout life. As the primary sensory neurons are responsible for detecting odors, they are exposed to pathogens and toxic substances that are inhaled into the nasal cavity. Thus primary sensory neurons frequently die off and are replaced by stem cells that line the base of the olfactory epithelium. Due to the numerous growth factors that OECs express, the newly generated axons successfully grow up into the olfactory bulb and make connections with the second order neurons. The ability of OECs to promote axon growth, migrate ahead of axons and interact with astrocytes has led them to become leading candidates for cell transplantation therapy to repair the injured spinal cord. After injury to the spinal cord, the inflammatory response and subsequent secondary degeneration creates a hostile environment for regenerating axons and the development of the fibrotic/astrocytic scar creates a physical barrier. By transplanting OECs into the injury site, they can interact with astrocytes to reduce the astrocytic scar and then the OECs can migrate to form a glial bridge to promote the growth of axons across the injury site. The ability of OECs, or OECs together with olfactory nerve fibroblasts, to facilitate the repair of the injured spinal cord has been demonstrated in rats (Li et al., 1997), dogs (Granger et al., 2012) and human (Tabakow et al., 2014). OECs are not all the same – which subpopulation is best for spinal repair? There are several subpopulations of OECs based on their anatomical locations, functions and the molecules that they express. In the main olfactory system, there are three subpopulations: (1) the peripheral OECs that ensheathe the bundles of axons as they project from the epithelium, (2) the OECs of the outer layer of the nerve fibre layer of the olfactory bulb, where the olfactory sensory axons def