Corticospinal neuron transplantation to repair chronic cervical spinal cord injury
Abstract
The corticospinal tract is comprised of neuron cell bodies that reside in the brain but extend nerve fibers down the length of the spinal cord. This nerve tract is responsible for voluntary motor function and therefore, the severing of these corticospinal nerve fibers during a cervical spinal cord injury leads to a loss or diminishment of this function. By repairing the corticospinal tract, voluntary motor function may be restored. Unfortunately, spinal cord injury causes cavities to form within the spinal cord that are then surrounded by scarring that limits natural regeneration of the severed nerve fibers. One approach to overcome this is to transplant cells within the spinal cord injury cavity that can act as a relay system to reconnect the severed ends of the corticospinal tract. For this to be possible, the transplanted cell needs to stably integrate and "communicate" with the injured corticospinal tract, meaning that it needs to display specific cell characteristics that closely match the identity of the neurons that make up the corticospinal tract. We have developed a characterized and reproducible strategy to create human cortical neurons from nonembryonic stem cells that match these characteristics. When transplanted into varying rat models of cervical spinal cord injury, these human cortical neurons fill the cavity, extend nerve fibers beyond the scarred border, promote regeneration of the rat s own severed nerve fibers, and ultimately lead to some restoration of motor function. This preliminary data is promising, but for this to be viable as a translational therapy, it is crucial that we know precisely how transplantation is operating within the injured cervical spinal cord (i.e., if these transplanted cortical neurons are truly acting as a relay system and integrating both anatomically and functionally into the severed corticospinal tract). In this project, we propose to transplant these human cortical neurons into a rat model of chronic cervical spinal cord injury; we will then use viruses coupled to fluorescent tags to map the relevant injured nerve tracts, the transplanted human cortical neurons, and functional connectivity between the two. In addition, we can correlate behavior with these subsequent anatomical changes by monitoring the rats biweekly for changes in sensory and motor function. This will provide us with important information as to how the nerve tracts responsible for voluntary motor function "rewire" in response to injury and transplantation, and whether transplanted human cortical neurons are capable of integrating into these chronically damaged nerve tracts. With this preliminary information, we can begin tailoring parameters to better promote regeneration and connectivity between the injured nerve tracts and the transplanted human cortical neurons and strengthen the relay system. We believe this project represents an integral first step in developing translational therapies that restore motor function by repairing the specific nerve tracts responsible for voluntary motor function. Developing therapies that seek to improve the sensorimotor deficits specific to chronic cervical spinal cord injury are desperately needed. Over 80% of spinal cord injury research is based on lower spinal injury models with the aim being to improve locomotion. However, surveys report that the top priority of quadriplegics is restoration of hand and arm function. As the motor circuits responsible for locomotion and voluntary hand/arm function are different, therapies that target cervical spinal cord injury would help directly address the desires and priorities of this demographic. Additionally, chronic therapies stand to benefit the largest number of civilians and military personnel currently living with an SCI and can address concerns specific to a "mature" injury (e.g., neuropathic pain and rewiring of neural circuitry). For military personnel injured in combat that must undergo several echelons of care p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810260
Entities
People
- Giles W. Plant
Organizations
- Stanford University
- United States Army