Developing a regeneration-based functional restoration treatment for spinal cord injury

One of the most exciting and challenging frontiers in neuroscience and medicine is to repair traumatic injuries to the central nervous system (CNS). Most spinal cord and head injuries result in devastating paralyses, yet very limited clinical intervention is currently available to restore the lost abilities. Traumatic injuries of the spine cause fractures and compression of the vertebrae, which in turn crush and destroy the axons, long processes of nerve cells that carry signals up and down the spinal cord between the brain and the rest of the body. It follows that the best chance for promoting functional recovery is identifying strategies that enable lesioned axons to regenerate and reconnect the severed neural circuits. Even minor improvements in voluntary motor functions after spinal cord injury could be immensely helpful for increasing the quality of life, employability, and independence, especially for patients with injuries at the upper spinal level. Thus, our overall research program centers on axon regeneration in general, with a focus on regenerating descending axons from the brain that control voluntary motor and other functions.

We recently made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system, which led to unprecedented extents of axon regeneration in various CNS injury models. While our success was compelling, we found that many regenerated axons were stalled at the lesion sites by the injury-induced glial scars. Furthermore, it is unclear whether the regenerated axons can form functional synaptic connections when they grow into the denervated spinal cord. This proposed research program is aimed at solving these obstacles by using human stem cell technologies. In the first aim, we will use human neural stem cells to engineer “permissive cell bridges” that can guide the maximum number of regenerating axons to grow across injury sites. In the second aim, we will test the therapeutic potential of human stem cell-derived neurons in forming “functional relays” that could propagate the brain-derived signals carried by regenerating axons to the injured spinal cord. Together, our research program is expected to develop a set of therapeutic strategies that have immediate clinical implications for human SCI patients.