Can an injured spinal cord be rebuilt? This is the question that drives basic research in the field of spinal cord injury. As investigators try to understand the underlying biological mechanisms that either inhibit or promote new growth in the spinal cord, they are making surprising discoveries, not just about how neurons and their axons grow in the CNS, but also about why they fail to regenerate after injury in the adult CNS. Understanding the cellular and molecular mechanisms involved in both the working and the damaged spinal cord could point the way to therapies that might prevent secondary damage, encourage axons to grow past injured areas, and reconnect vital neural circuits within the spinal cord and CNS. There has been successful research in a number of fields that may someday help people with spinal cord injuries. Genetic studies have revealed a number of molecules that encourage axon growth in the developing CNS but prevent it in the adult. Research into embryonic and adult stem cell biology has furthered knowledge about how cells communicate with each other. Basic research has helped describe the mechanisms involved in the mysterious process of apoptosis, in which large groups of seemingly healthy cells self-destruct. New rehabilitation therapies that retrain neural circuits through forced motion and electrical stimulation of muscle groups are helping injured patients regain lost function. Researchers, many of whom are supported by the National Institute of Neurological Disorders and Stroke (NINDS), are focused on advancing our understanding of the four key principles of spinal cord repair:
Protecting surviving nerve cells from further damage
Replacing damaged nerve cells
Stimulating the regrowth of axons and targeting their connections appropriately
Retraining neural circuits to restore body functions
A spinal cord injury is complex. Repairing it has to take into account all of the different kinds of damage that occur during and after the injury. Because the molecular and cellular environment of the spinal cord is constantly changing from the moment of injury until several weeks or even months later, combination therapies will have to be designed to address specific types of damage at different points in time.
Researchers are experimenting with cell grafts transplanted into the injured spinal cord that act as bridges across injured areas to reconnect cut axons, or that supply nerve cells to act as relays. Several types of cells have been studied for their potential to promote regeneration and repair, including Schwann cells, olfactory ensheathing glia, fetal spinal cord cells, and embryonic stem cells. In one group of experiments, investigators have implanted tubes packed with Schwann cells into the damaged spinal cords of rodents and observed axons growing into the tubes. One of the limitations of cell transplants, however, is that the growth environment within the transplant is so favorable that most axons don’t leave and extend into the spinal cord. By using olfactory ensheathing glia cells, which are natural migrators in the PNS, researchers have gotten axons to extend out of the initial transplant region and into the spinal cord. But it remains to be seen whether or not regenerated axons are fully functional.
Fetal spinal cord tissue implants have also yielded success in animal trials, giving rise to new neurons, which, when stimulated by growth-promoting factors (neurotrophins), extend axons that stretch up and down several segments in the spinal cord. Animals treated in these trials have regained some function in their limbs. Some patients with long-term spinal cord injuries have received fetal tissue transplants but the results have been inconclusive. In animal models, these transplants appear to be more effective in the immature spinal cord than in the adult spinal cord. Stem cells are capable of dividing and yielding almost all the cell types of the body, including those of the spinal cord. Their potential to treat spinal cord injury is being investigated eagerly, but there are many things about stem cells that researchers still need to understand. For example, researchers know there are many different kinds of chemical signals that tell a stem cell what to do. Some of these are internal to the stem cell, but many others are external – within the cellular environment – and will have to be recreated in the transplant region to encourage proper growth and differentiation. Because of the complexities involved in stem cell treatment, researchers expect these kinds of therapies to be possible only after much more research is done. Researchers are also looking at ways to compensate for axons that, having lost their myelin sheaths, have a decreased ability to conduct the electrical impulses essential for axonal communication. Preliminary studies with compounds known as potassium channel blockers, which block the flow of ions through the demyelinated membrane and increase the potential for messages to get through, have shown some success, but mostly in terms of reducing spasticity in muscles. Further studies might show how remyelinating axons could also improve function.
Stimulating regrowth of axons
Stimulating the regeneration of axons is a key component of spinal cord repair because every axon in the injured spinal cord that can be reconnected increases the chances for recovery of function. Research on many fronts reveals that getting axons to grow after injury is a complicated task. CNS neurons have the capacity to regenerate, but the environment in the adult spinal cord does not encourage growth. Not only does it lack the growth-promoting molecules that are present in the developing CNS, it also contains substances that actively inhibit axon extension. For axon regeneration to be successful, the environment has to be changed to turn off the inhibitors and turn on the promoters. Investigators are looking for ways to take advantage of the chemicals that drive or halt axon growth: growth-promoting and growth-inhibiting substances, neurotrophic factors, and guidance molecules. In the developing CNS, thread-like axons grow and lengthen behind the axonal growth cone, an active tip only a few thousandths of a millimeter in diameter, which interacts with chemical signals that encourage growth and direct movement. But the environment of the adult CNS is hostile to axon growth, primarily because growth-inhibiting proteins are embedded in myelin, the insulating material around axons. These proteins appear to preserve neural circuits in the healthy spinal cord and keep intact axons from growing inappropriately. But when the spinal cord is injured, these proteins prevent regeneration. At least three growth-inhibitory proteins operating within the axonal tract have been identified. The task of researchers is to understand how these inhibitory proteins do their job, and then discover ways to remove or block them, or change how the growth cone responds to them. Growth-inhibiting proteins also block the glial scar near the injury site. To get past, an axon has to advance between the tangles of long, branching molecules that form the extracellular matrix. A recent experiment successfully used a bacterial enzyme to clear away this underbrush so that axons could grow.
A treatment that combines both these approaches – turning off growth-inhibiting proteins and using enzymes to clear the way – could create an encouraging environment for axon regeneration. But before trials of such a treatment can be attempted in patients, researchers must be sure that it could be controlled well enough to prevent dangerous miswiring of regenerating axons. Neurotrophic factors (or neurotrophins) are key nervous system regulatory proteins that prime cells to produce the molecular machinery necessary for growth. Some prevent oligodendrocyte death, others promote axon regrowth and survival, and still others serve multiple functions. Unfortunately, the natural production of neurotrophins in the spinal cord falls instead of rises during the weeks after injury. Researchers have tested whether artificially raising the levels post-injury can enhance regeneration. Some of these investigations have been successful. Infusion pumps and gene therapy techniques have been used to deliver growth factors to injured neurons, but they appear to encourage sprouting more than they stimulate regeneration for long distances. Axonal growth isn’t enough for functional recovery. Axons have to make the proper connections and re-establish functioning synapses. Guidance molecules, proteins that rest on or are released from the surfaces of neurons or glia, act as chemical road signs, beckoning axons to grow in some directions and repelling growth in others. Supplying a particular combination of guidance molecules or administering compounds that induce surviving cells to produce or use guidance molecules might encourage regeneration. But at the moment, researchers don’t understand enough about guidance molecules to know which to supply and when.
Researchers hope that combining these strategies to encourage growth, clear away debris, and target axon connections could reconnect the spinal cord. Of course, all these therapies would have to be provided in the right amounts, in the right places, and at the right times. As researchers learn more and understand more about the intricacies of axon growth and regeneration, combining therapies will become a powerful treatment for spinal cord injury.
The Working 2 Walk 2012 Science & Advocacy Symposium will feature presentations and small-group discussions with the worlds leading research scientists and community advocates in the field of SCI.