This site will provide you with information pertinent to your understanding of applied regeneration following SCI. It is important that you follow the links on this page to further understand the material. Information on this site was taken from the NINDS website, 2006
1. TRANSPLANTATION
One approach for repairing spinal cords that is being tested in animals is to transplant cells and tissues into the damaged spinal cord. In particular, scientists are transplanting cells or pieces of peripheral nerves that produce substances that create an environment for axons to grow. This idea was first advocated about 100 years ago by the neurologist Ramón y Cajal. He suggested implanting cells from the PNS into the area of a CNS injury. Since the environment of the PNS supports axon regeneration, he believed re-creating this environment in the spinal cord might allow CNS axons to regrow after an injury. Ideally, this environment would also point growing nerves to the correct targets. Experiments with PNS transplants in rat models of spinal cord injury have led to axon elongation and cell body changes associated with regrowth. Transplants from the PNS also seem to reduce scarring around the injury that may impede regrowth. One technique tested in rats is transplanting Schwann cells -- glial cells that help myelinate axons in the PNS -- into the spinal cord after injury. These transplants supported regrowth of the damaged nerves in rats with spinal cord injury. Researchers are now studying human Schwann cells to determine if this technique will work in humans.
Another way of encouraging regeneration is to implant fetal tissue. Tissue from a growing fetus contains stem cells, progenitor cells, and many substances that support growth. Such tissue also presents fewer obstacles to growing axons. Stem cells can differentiate into several cell types, depending on the signals they receive. Transplanting them into the spinal cord may, with the right chemical signals, help them develop into neurons and supporting cells in the spinal cord, re-establishing lost circuits.
Studies in rats show that fetal transplants promote survival and regrowth of some damaged nerve cells. Transplanting fetal CNS tissue into the spinal cord of both mature and newborn rats yielded axon growth that terminated within a few millimeters of the border of the transplant. Researchers still need to learn exactly how fetal tissue transplants promote nerve regrowth. The transplants appear to "rescue" axons and provide a bridge across which regenerating axons can grow. While both adult and newborn rats regrew descending nerve fibers from the brain, the growth of descending pathways into the transplants was substantially greater in the newborns. This suggests that other changes in the maturing CNS, such as the production of inhibitory factors or a loss of certain axon guidance molecules, may influence axonal regrowth after injury.
Stem Cell Basics - please work your way through the
seven sections
Olfactory Ensheathing
Cells - article
2. TROPHIC FACTORS
Using insights from retina and culture experiments, researchers are beginning to test whether trophic factors can enhance regrowth in the spinal cords of rats. Growth factors may be responsible for much of the nerve regeneration normally seen in the PNS and in CNS axons near transplanted PNS tissue.
Different pathways in the spinal cord may require particular combinations of growth factors for survival after injury. While nerve cells usually do not survive after axons have been severed close to the cell body, recent experiments in the rat spinal cord have shown that two trophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3), can rescue nerve cells from which the axons have been recently severed. Although NT3 has short-term effects, BDNF can help nerve cells survive for 4 weeks or more after injury. When the trophic factors BDNF, NT3, and NT4 (neurotrophin 4) were combined with fetal tissue transplants, axons no longer stopped growing at the border of the transplant but instead greatly expanded the territory into which they projected.
The combination of transplants and trophic factors also led to an increase in c-jun, an important immediate early gene. Immediate early genes respond rapidly to many stimuli and regulate many cell functions. Interestingly, these experiments showed that axons from cells that use the neurotransmitter serotonin responded to trophic factors more vigorously than axons from cells that use other neurotransmitters. This illustrates the importance of finding the right combination of growth factors for each type of cell.
3. COMBINATION FACTORS
Evidence that combining some therapies may have an additive effect has prompted researchers to focus effort on finding a combination that will achieve regeneration. Some combination therapies recently tested in rats have shown exciting results. One approach used neurotrophin 3, fetal cell transplants, and IN-1, the antibody to myelin-associated neurite growth inhibitor. Rats treated with this approach showed faster and more extensive recovery after spinal cord injury than those given any single treatment alone. Their recovered reflexes disappeared after researchers destroyed the cerebral cortex, showing that the brain, rather than reorganization within the spinal cord, controlled the reflexes. Researchers still need to learn if this therapy can be a general approach or if specific nerve pathways have specific requirements for growth. They also need to carefully define the time windows for effective combination treatment.
Another approach using nerve fiber transplantation combined with growth factors showed the first functional regeneration of completely transected rat spinal cords. Researchers carefully transplanted 18 pieces of peripheral nerves (one to three pieces for each of the normal nerve tracts) taken from the rats' chests to "bridge" 5-millimeter gaps at the T8 segment of rats' spinal cords. To evade inhibitory proteins from oligodendrocytes, the bridges routed regenerating axons away from white matter, where they would normally grow, and into gray matter. The researchers fixed the grafts in place with a glue based on a blood-clotting factor called fibrin. The glue also contained acidic fibroblastic growth factor, or aFGF, which enhances nerve fiber development. Finally, the scientists wired the vertebrae to keep the spine in place while the area healed.
After 3 weeks, rats that had received this type of graft began to recover function in their hind legs. Some of the treated rats regained some movement on both sides of their bodies, while others regained movement on only one side. The rats that recovered on both sides of their bodies eventually began partially supporting their weight with their hind limbs. They also displayed walking movements and contact-placing reflexes. The rats continued to improve gradually over the course of a year, though they never walked normally. Rats with bridges from white matter to other white matter, rats in which the fibrin glue had no aFGF, and rats that did not receive transplants did not recover any function over time.
Anatomical studies of spinal cords from rats that recovered function after this therapy showed that the nerve fibers grew into the gray matter on the opposite side of the gap. The fibers then grew at the interface between the gray matter and the white matter, an area that corresponds to the normal corticospinal tract in rats. The degree of recovery corresponded significantly to the degree of motor fiber regeneration.