image: ©HadelProductions | iStock
Scientists at the Gladstone Institutes have demonstrated that human stem cell-derived spinal interneurons can successfully integrate into injured spinal cord networks in rats, restoring vital breathing-related motor functions
Overcoming barriers in neural regeneration
Traumatic spinal cord injuries, particularly those occurring in the cervical neck region, disrupt critical neural pathways between the brainstem and the diaphragm, often causing permanent respiratory impairment. Because the central nervous system lacks a natural mechanism to rebuild lost connections, no approved therapies currently exist to restore damaged circuits.
To address this, researchers focused on V2a interneurons, specialised relay cells that act as biological jumper cables across damaged neural pathways to carry motor signals.
Laboratory engineering and cell processing
The research team spent eighteen months refining a protocol recipe to differentiate human induced pluripotent stem cells into transplantable V2a interneurons:
- Stem cell lineage:
- Building on a decade of early rodent stem cell models, the team successfully engineered human V2a interneurons tailored for cervical circuit repair.
- Cryopreservation capability:
- Researchers verified that the engineered cells can be frozen in vials and thawed later without losing viability, a crucial requirement for future clinical applications.
Integration into host circuits
One week after inflicting cervical spinal cord injuries in adult rats, researchers transplanted the engineered human interneurons into the lesion sites:
- Synaptic integration:
- Two months post-transplantation, the human cells survived the hostile local environment and formed functional synaptic connections with both brainstem projections and nearby host neurons.
- Diaphragm activation:
- Stimulating the transplant site triggered measurable electrical activity in the rats’ diaphragms, confirming physical connection into the host respiratory circuit.
Respiratory recovery under stress
While breathing differences appeared subtle under baseline conditions, significant functional gains emerged when the animals faced physiological challenges:
- Stress testing:
- Rats were exposed to low-oxygen (hypoxia) and high-carbon-dioxide (hypercapnia) environments, forcing their respiratory systems to work harder.
- Survival and protection:
- Most injured, untreated control rats experienced respiratory failure during these challenges. Conversely, 75% of the rats that received V2a interneuron transplants passed without difficulty, demonstrating that the cells provided crucial reserve capacity.
Future translation and clinical goals
Before human clinical trials can begin, the team must demonstrate efficacy in larger animal models and evaluate whether the treatment remains effective when delivered months or years after an injury.
Beyond respiratory restoration, researchers are adapting the technique to target neural circuits that govern arm and hand movement.