Engineered Human Spinal Interneurons Restore Breathing Function in Injured Rats, Paving Way for Regenerative Therapies
核心洞察
Human stem cell–derived V2a interneurons (搜索) survived transplantation in rats with cervical spinal cord injury (搜索) and formed functional connections with host neural circuits.
Three-quarters of treated rats passed respiratory challenge tests that caused respiratory failure in most untreated injured animals, demonstrating meaningful functional recovery.
The Gladstone Institutes (搜索) team identified a specific subset of transplanted V2a interneurons (搜索) particularly likely to integrate with host breathing circuits, offering a path toward optimized cell therapies.
Spinal cord injuries affect an estimated 15 to 20 million people worldwide, often causing lasting impairments in movement, sensation, and independence. When such injuries occur at the level of the neck, damaged spinal circuits can disrupt signals controlling the diaphragm—the primary muscle for breathing. Despite advances in emergency care and rehabilitation, no approved therapies exist to rebuild the neurons and connections lost after a spinal cord injury (搜索). Now, new research from scientists at Gladstone Institutes (搜索) offers a promising step toward a regenerative treatment.
The study, published in Science Translational Medicine, demonstrates that human stem cell–derived spinal interneurons—specifically V2a interneurons (搜索) critical for breathing and movement—can survive transplantation in injured rats, connect with the animals' own neural circuits, and improve breathing-related motor function.
Engineering the Right Cell Type
The spinal cord contains many types of interconnected neurons, or interneurons, which act like biological jumper cables linking neurons that need to communicate across a circuit. The Gladstone team, led by first author Lana Zholudeva, PhD, focused on V2a interneurons (搜索), relay cells involved in controlling movement that previous research has implicated in recovery after traumatic spinal cord injury (搜索).
Building on nearly a decade of work, the team refined methods to create transplantable human V2a interneurons (搜索) from induced pluripotent stem cells, optimized for repairing injured spinal circuits. "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," said Deepak Srivastava, MD, President and Senior Investigator at Gladstone and senior author of the study. The researchers also ensured the final cells could be frozen and later thawed for use—a key factor for eventual clinical translation.
Transplantation and Functional Recovery
Zholudeva and colleagues transplanted the human spinal interneurons into adult rats one week after injury to the cervical spinal cord, the neck region where injuries are among the most common in people and frequently disrupt breathing circuits. "Breathing is evolutionarily conserved across many species, very well-defined anatomically and functionally, and directly relevant to people living with high-level spinal cord injury (搜索)," Zholudeva explained. "It was the ideal circuit to serve as a test bed."
Two months after transplantation, the new cells had not only survived the hostile injury environment but had formed connections with nearby cells in the spinal cord. When researchers activated the transplant site, they observed increased diaphragm activity. Separately, activating the rats' own brainstem neurons caused the transplanted cells to switch on in response.
Under normal conditions, breathing differences were subtle. However, when challenged with low oxygen or high carbon dioxide—conditions forcing the diaphragm to work harder—most injured, untreated rats showed signs of respiratory failure. In contrast, three-quarters of the rats that received the new V2a interneurons (搜索) passed the challenges without difficulty.
"That's 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," Zholudeva said. "The transplanted cells seem to be providing that additional capacity."
Toward Human Translation
The research team also took a first look at why some transplants worked better than others, identifying a specific subset of transplanted V2a interneurons (搜索) that appeared especially likely to connect with the host breathing circuit and therefore important for recovery. They plan to follow up on that finding and continue studying how to make the cells most needed for repair.
Before the cell therapy can be tested in people, the team must demonstrate efficacy in larger animals and assess whether it works in the injured spinal cord months or years after injury, not just in the early days. The scientists are also working to extend the approach beyond breathing to circuits controlling arm and hand function, which 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."