The therapeutic potential of glia for neural repair

Abstract

The central nervous system has a very limited capacity to regenerate after injury such that spinal cord injuries often result in permanent loss of function. The main factor hampering neuronal regeneration after injury is the inability of regenerating neurons to reach their target due to inflammatory and inhibitory factors, oxidative stress and glial scarring. It is therefore important that we determine the best approaches for developing neural regeneration therapies. One approach is to transplant glia, which are supporting cells crucial for the survival and growth of all neurons. The glia of the olfactory system, called olfactory ensheathing cells (OECs), have many properties that make them excellent candidates for neural repair therapies: they naturally exist within both the peripheral and central nervous system, they interact with astrocytes, and express many neurotrophic molecules. Transplantation of OECs into the injured spinal cord has been trialled in many animal models with some promising results, and it has been shown to be safe in a phase I clinical human transplant trial. However, OECs are not a uniform population but instead there are different subpopulations each with a different molecular profile and proposed roles in vivo. We have determined that axons respond differently to OECs derived from the peripheral region of the olfactory nerve or from the olfactory bulb. We have also shown that OECs from anatomically distinct regions of the olfactory bulb are a functionally heterogeneous population with distinct differences during cell-cell contact. In contrast, OECs from the peripheral nerve have a uniform behaviour during cell-cell contact. These behaviours are consistent with their proposed roles in vivo. What is yet to be determined is which subpopulation of OECs has the most potential for neural repair therapies. We have also determined that OECs actively phagocytose axonal debris as well as bacteria, characteristics which add to their potential benefit for neural repair therapies. We have also screened molecules that could be combined with OECs to stimulate their proliferation and migration and found that the natural product, curcumin, dramatically increases the proliferation, migration and cell-cell contact of OECs. Together, these results show that OECs are a heterogeneous population of cells with characteristics that can potentially enhance axon regeneration within the injured central nervous system.