Combination of Rehabilitative Training with Neural Stem Cell Transplantation
Funded in: 2014, 2015, 2016
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Problem: Despite successful axon growth after neural stem cell (NSC) transplantation, recovery of locomotor function is limited.
Target: Locomotor training might drive remodelling of axon connections from the NSC graft to host neurons
Goal: Development of a combined therapy using stem cell grafts with rehabilitative training
Spinal cord injury (SCI) is a devastating condition that can affect motor, sensory and autonomic function due to disruption of axons that connect the brain to the spinal cord. Despite recent advances in promoting axonal regeneration after SCI, the achievement of functional recovery after severe injury remains a formidable challenge.
Previously, the project team showed that multipotent neural stem cells (NSC) grafted to the site of injury of a complete spinal cord transection extend thousands of axons over the length of the central nervous system. These graft-derived axons make synaptic contacts with host neuronal targets, forming a bridge across the injury site to potentially restore the connection between brain and spinal cord. However, grafted animals show limited recovery of hindlimb locomotion, leaving substantial room for improvement. This limited recovery could be attributed to weak or suboptimal connections between graft-derived axons and host neurons. Therefore, additional activity-dependent modulation could improve motor function.
Rehabilitative training, like physical therapy in patients, can be used to improve locomotor function in injured rats by reshaping and strengthening spinal cord circuitry. Thus, it is hypothesized that use of locomotor training will drive remodelling of axon connections from the NSC graft to host neurons, thereby optimizing novel neural relays and enhancing functional outcome after severe SCI.
Treadmill step training has been successfully translated from animal studies to clinical trials in SCI. Therefore, this project will study the contribution of manual-assisted bipedal treadmill training to locomotor recovery of rats after a low-thoracic complete transection and NSC graft. The aim is to understand how activity-driven plasticity modifies synaptic connections between graft-derived axons and host neurons and how this is translated into locomotor improvement.
This project will contribute to the development of a combined therapy using stem cell grafts with rehabilitative training to optimize locomotor recovery after a severe injury.