About 15 to 20 million people globally are impacted by spinal cord injuries, which can impair movement, limit their independence, and disrupt important bodily functions. For example, damage to the spinal cord that occurs at the neck disrupts signals that control the diaphragm, the main muscle used in breathing. The body does not naturally rebuild lost neural connections and there are no approved therapies that can regenerate the neurons and connections affected by a spinal cord injury. But that could change thanks to new research from scientists at Gladstone Institutes. 

Full details of the work, which was done in rats, are published in Science Translational Medicine in a new paper “Human spinal interneurons repair the injured rat spinal cord through synaptic integration.” It shows that human stem cell-derived spinal interconnected neurons or interneurons—critical cells for breathing and movement—can survive following transplantation in injured rats, form connections with the receiving animals’ neural circuits, and improve breathing-related motor function. As Lana Zholudeva, PhD, a Gladstone investigator and the paper’s first author, puts it, “this study demonstrates that a specific type of human spinal interneuron can be engineered from stem cells and transplanted into an injured spinal cord” in such a way that “the cells not only survive, but form new pathways to repair damaged networks.”

For the study, the scientists focused on a subtype of the interneurons called V2a interneurons. These are relay cells that play a role in controlling movement. Previous research by Zholudeva’s team and others have shown that these cells are implicated in recovery after traumatic spinal cord injury, including in the neural circuits involved in breathing and walking. 

Using human induced pluripotent stem cells, Zholudeva and her team generated transplantable human V2a interneurons that were optimized for repairing injured spinal circuits. Specifically, “we engineered human V2a-enriched SpINs from an optogenetic channelrhodopsin-2 (ChR2) expressing the human induced pluripotent stem cell line,” they wrote in the paper. Getting the process right took some doing, according to Deepak Srivastava, MD, Gladstone president and senior author of the study “it took about a year and a half of trial and error to get the recipe right to make this particular neuron out of stem cells, but it really paid off.” They also ensured that cells could be frozen in vials and later thawed for use, making it possible to use them in human clinical trials down the road. 

Next, the scientists transplanted the interneurons into adult rats one week after they sustained injuries to their cervical spinal cords. Two months post transplantation, the scientists found that the new cells not only survived the hostile environment of the injury site but also formed connections with nearby cells. Furthermore, when the scientists activated the transplant site, they observed increased activity in the diaphragm. They also activated the rats’ own brainstem neurons and found that the transplanted cells switched on in response. 

The scientists also tested the rats’ breathing under different conditions. Under normal conditions, the difference in the animals’ breathing was less noticeable. But in a low oxygen or high carbon dioxide environment, most of the injured, untreated controls showed signs of respiratory failure. In contrast, most of the rats that received the new V2a interneurons passed the challenges without difficulty. “The transplanted cells seem to be providing that additional capacity,” Zholudeva said. 

One component of the study involved looking at why some transplants worked better than others. The scientists identified a specific subset of transplanted V2a interneurons that seemed especially likely to connect with the host animal’s breathing circuit. They plan to follow up on the finding as part of their next steps. Further down the road, they plan to test the potential therapy in larger animals. And they will evaluate whether it is as effective in the injured spinal cord months or years after injury, not just in the immediate aftermath. 

The team also hopes to test the treatment in other neural circuits. Specifically, they are considering circuits that control arm and hand function, something that people with cervical spinal cord injuries often identify as their highest priority for recovery. “We’ve shown a proof of principle that this can work, that you can engineer a defined cell type, transplant it, and have it actually repair a specific circuit,” Zholudeva said. “Now we have to make it work more consistently, in more circuits, and eventually in people.”

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