Spinal Cord Injury: Regeneration

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TROPHIC FACTORS

Maintenance of neurons depends on survival signals that target cells produce in limited amounts. Rita Levi-Montalcini and Viktor Hamburger discovered nerve growth factor (NGF) in the 1950s. NGF is essential for survival of many neural cell types. It probably does not act as a chemo-attractant, directing where axons grow, but maintains their survival once they reach their targets.

In a study of rat neural cells grown in culture for 30 days, those that were exposed to high levels of NGF survived at a much higher rate than those grown at low concentrations of NGF (Chun & Patterson, 1977).

NGF is actually only one of several neurotrophins, each of which act to promote the survival of specific neuronal subtypes. NGF is secreted by peripheral target cells, and is thus involved in the maintenance of motor neurons. Brain-derived neurotrophic factor (BDNF), as its name suggests, is secreted by cells within the CNS, and thus promotes the survival of sensory neurons.

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PERIPHERAL NERVOUS SYSTEM REPAIR

Damage to the peripheral system occurs every time you cut your finger, and the body is well adapted to repair damage not contained in the brain and spinal cord. Damage to the central nervous system, however, is much more rare, and the body does not have the same mechanisms for re-growth. In the peripheral nervous system, injury leads to an immune response to quickly clean up damaged tissue as the axon degenerates downstream from the site of injury. The injured neurons begin producing growth-promoting genes, and the axon starts to grow again. Support cells called Schwann cells promote axon growth along the original path to target cells by secreting neurotrophins and providing a surface for the axon to grow along. Interfering debris clean up in the central nervous system is less efficient, leading to a lot of the secondary damage incurred during spinal cord injury. Instead of promoting new growth, central nervous system support cells secrete inhibitory factors. Central nervous system axons generally fail to regenerate after injury.

If CNS neurons encounter an environment like in the PNS, they might be able to regenerate. Implanting peripheral nervous tissue and even just the glial cells that support regeneration in the periphery, is a promising direction in the field of CNS regeneration. As early as 1911, researchers discovered that implanting sections of PNS tissue into the spinal cord and brain led to neuron growth in rats. Implantation of glial precursor cells (cells that are specified to become peripheral support cells), leads to the formation of growth cones on CNS axons in animal models. If given the correct signals, many CNS neurons have the capacity to grow long distances.

Failure of the CNS neurons to grow under normal conditions is mainly due to growth inhibition molecules. The most significant of these molecules is myelin-associated neurite growth inhibitor, which is present on the surface of CNS glial cells. In the lab, axons will grow across glial cells only if these growth inhibitors are deactivated. Blocking glial neurite inhibitors in rats allowed them to grow axons after injury leading to improvements in their motor performance, but not perfect regeneration of complex pathways. While growth can occur when these inhibitory molecules are blocked, the CNS circuits do not always regenerate with the correct connections. Axon guidance and synapse formation are still unsolved puzzles.

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TRANSPLANTS IN THE SPINAL CORD

By transplanting healthy developing neurons into the CNS, growth can be reestablished even after normal neural growth is complete. The age of the transplanted neurons is important; they must still be young enough to grow and take on new fates. The greater the damage incurred in the transplantation process, the less likely the cells are to grow properly, so it is crucial to develop non-disruptive surgery techniques if this method is to be used in human patients. Unfortunately, it appears that the damaged system is less able to support growth than the normal healthy CNS. The action of inhibitory factors and immune system activity mean that regeneration in the damaged system can only occur with additional intervention, not just transplanted growing neurons.

Neurons from the olfactory system (within the CNS) constantly regenerate and are ensheathed in glia that share characteristics of CNS and PNS support cells. Transplanting these support cells into the spinal cord not only promotes growth in the spinal cord neurons, but also promotes target cell innervation. This is an advantage over PNS tissue transplants. Lab rats undergoing this procedure after spinal cord damage were able to regain motor control of their paws.

Neural stem cells are another promising solution for regeneration. It has long been thought that the CNS did not contain stem cells, but recent studies have found that it does. These cells can be maintained almost indefinitely in culture and would eliminate the need for fetal neural tissue for a source of undeveloped neurons. The ethical concerns of stem cell research and the source of these cell lines must be addressed, but the potential in this are of research is significant.

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