Approximately 15 to 20 million individuals globally experience spinal cord injuries, frequently resulting in permanent limitations in mobility, sensory function, and autonomy. Injuries located in the cervical region can be particularly catastrophic, as compromised spinal pathways interfere with neural signals governing the diaphragm—the primary muscle responsible for respiration.
Despite progress in urgent medical care and recovery methods, there are currently no approved treatments to regenerate the neurons and connections lost due to spinal cord injuries. However, new research from the Gladstone Institutes provides hope for future regenerative therapies.
Breakthrough in Spinal Cord Repair
The study, published in Science Translational Medicine, shows that human stem cell-derived spinal interneurons – cells that are critical for breathing and movement – can survive after being transplanted in injured rats, connect with the animals’ own neural circuits, and improve breathing-related motor function.
Lana Zholudeva, PhD, a Gladstone investigator and first author of the new study, states that spinal cord injuries have long been considered difficult to repair because the body does not naturally rebuild the neural connections that are lost. This study demonstrates that a specific type of human spinal interneuron can be engineered from stem cells and transplanted into an injured spinal cord, where the cells not only survive, but form new pathways to repair damaged networks.
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The spinal cord is composed of various interconnected neurons, known as interneurons, which act like biological connectors, helping neurons communicate across circuits. The Gladstone team focused on a specific type called V2a interneurons, which are key for controlling movement.
Earlier research by Zholudeva’s team and others globally found that these cells play a role in recovery after severe spinal cord injuries, particularly in circuits related to breathing and walking. To test if transplanting new V2a interneurons could aid spinal cord healing, Zholudeva’s team first developed methods to produce these cells in a lab setting.
Creating Transplantable Human V2a Interneurons
The process began through collaborations among Zholudeva, Michael Lane, PhD, Shelly Sakiyama-Elbert, PhD, and former Gladstone scientist Todd McDevitt, PhD. Initially, they used mouse embryonic stem cells to generate specific spinal neuron populations. This approach has since shifted toward using human induced pluripotent stem cells, which are more relevant for clinical applications.
At Gladstone, Zholudeva and her colleagues refined these methods to create human V2a interneurons suitable for transplanting into injured spinal cords. Deepak Srivastava, MD, Gladstone’s President and a senior researcher on the study, noted that perfecting the process to create these neurons from stem cells took about a year and a half but was well worth the effort.
The researchers also made sure the final cells could be frozen in vials and then later thawed for use, a key factor that could ultimately allow the cell therapy to be usable in a human clinical trial. Zholudeva and her colleagues transplanted the human spinal interneurons into adult rats one week after an injury to the cervical spinal cord.
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Injuries in the neck region are among the most common spinal cord injuries in humans and often disrupt the neural circuits controlling breathing. Two months after transplantation, the new cells survived the harsh injury environment and formed connections with nearby spinal cord cells.
When the researchers activated the transplant site, they observed increased diaphragm activity. Additionally, activating the rats’ brainstem neurons, which connect the brain to the spinal cord, caused the transplanted cells to respond. Under normal conditions, the difference in breathing was subtle.
However, when exposed to low oxygen or high carbon dioxide – conditions that force the diaphragm to work harder, most of the injured, untreated rats showed signs of difficulty. The transplanted cells seem to be providing additional capacity.
Zholudeva states that the difference between an injured person who gets a cold and ends up back on a ventilator, versus someone with enough function to handle that challenge, is significant. Before the cell therapy can be tested in people, the team will need to show it’s effective in larger animals and test whether it can work just as well in the injured spinal cord months or years after injury, not just in the early days after an injury. The scientists are also working to extend the approach beyond breathing to circuits that control arm and hand function, which people with cervical spinal cord injuries often identify as their highest priority for recovery.
