August 8, 2010
Boston, Mass. - Researchers for the first time have induced robust regeneration of nerve tissue connections in injured adult spinal cord sites that control voluntary movement. These findings provide hope that it may be possible to design therapies for paralysis and other impairments of motor function arising from spinal cord injury.
In rodent studies, the Children's Hospital Boston, UC Irvine, and UC San Diego team made this breakthrough by turning back the developmental clock in a molecular pathway critical for the growth of nerves in the corticospinal tract. The corticospinal tract is a bundle of nerves connecting the brain and spinal cord. While some degree of nerve regeneration has been achieved in other regions of the mature central nervous system (CNS), adult corticospinal nerves have been particularly resistant to regeneration after injury.
The corticospinal nerve regeneration was achieved by deleting PTEN, an enzyme that acts as a critical brake on cell growth. One of the key growth molecules whose activity can be reined in by PTEN is mTOR. In early stages of life, PTEN activity is low, allowing mTOR to promote developmental growth processes. In later stages, PTEN activity is increased and mTOR activity is decreased so that growth is more restricted.
In looking how to restore early developmental-stage cell growth in injured CNS tissue, Zhigang He, a neurology associate professor at Children's Hospital Boston -working with Mustafa Sahin, also of the Children's Neurology Department- showed in a 2008 study that modulating the PTEN/mTOR pathway enabled regeneration of new connections from the eye to the brain after optic nerve damage. He now partnered with Oswald Stewart from UCI and Binhai Zheng of UCSD to use the same approach to induce nerve regeneration in injured spinal cord sites.
Results of their study appear in the Aug. 8 online edition of Nature Neuroscience.
Nerve regeneration in mouse spinal cord. Deletion of the enzyme PTEN allows corticospinal nerves - which control voluntary movement - to regenerate past a lesion site.
"Until now, such nerve regeneration has been impossible in the spinal cord," says Oswald Steward, anatomy & neurobiology professor and director of the Reeve-Irvine Research Center at UCI. "Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a pathway to develop a therapy to induce regeneration of nerve connections following spinal cord injury in people."
In addition to extending optic nerve findings to the spinal cord, He points out that the current study makes the advance of showing that the regenerating nerves actually make anatomical connections with other nerve cells beyond the lesion site.
"We demonstrate that the regenerating nerves can form synapses in the spinal cord," he says. Synapses are the points of contact between nerve cells, crucial for transmitting signals. Synapses in the spinal cord allow nerve impulses from the brain to be conveyed to the limbs and other regions of the body.
Spinal cord injuries are due primarily to the interruption of connections between the brain and spinal cord. An injury the size of a grape can lead to a complete loss of function below the level of the injury. For example, an injury to the neck can cause complete paralysis of arms and legs, loss of ability to feel below the shoulders, loss of ability to control the bladder and bowel, loss of sexual function and secondary health risks including susceptibility to urinary tract infections, pressure sores and blood clots due to inability to move the legs.
Approximately 2 percent of American has some form of paralysis as a result of spinal cord injury, according to Christopher & Dana Reeve Foundation data.
"These devastating consequences occur even though the spinal cord below the level of the injury is intact," Steward says. "All these lost functions could be restored if we could find a way to regenerate the connections that were damaged."
He, Steward and their colleagues are now asking whether the PTEN-deletion treatment leads to restoration of motor function in mice with spinal cord injury. While the finding of anatomical connections between regenerating nerves and nerve cells beyond the lesion site is encouraging, in order for nerve regeneration to result in restoration of motor function the anatomical connections must represent real sites of information transfer.
"We are closely collaborating with Os's lab in studying functional recovery after spinal cord injury," says He.
Much further study is also needed to translate these findings into therapeutic strategies because PTEN is a tumor suppressor and is known to control numerous important cellular functions beyond nerve regeneration, He explains. A PTEN-targeted therapy would have to be delivered transiently and in a location-specific manner. Future studies may explore the efficacy of combining therapeutic approaches that target growth inhibitory molecules within nerve cells, like PTEN, with approaches that target the external growth inhibitory molecules found at CNS lesion sites.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.