Impaired breathing is a devastating consequence of cervical spinal cord injury (SCI), representing a significant burden to injured people and increasing the risk of mortality. Respiratory dysfunction and associated secondary complications remain the leading cause of morbidity and mortality in people with cervical SCI. Particularly concerning are reports indicating that the number of cervical SCIs has increased in recent years. While there is mounting clinical and experimental evidence for spontaneous improvements in respiration, the extent of recovery ? or functional plasticity ? remains incomplete. However, plasticity is reliant on spared neural substrates after incomplete spinal cord injury (SCI). Thus, the extent of recovery without therapeutic intervention and anatomical repair is limited. To address this limitation, and amplify plasticity and recovery of breathing following cervical SCI, the proposed work aims to use a novel cell therapy to promote repair of phrenic motor pathways that control function of the diaphragm ? a respiratory muscle essential to breathing. Results from our recent experimental studies have demonstrated that transplantation of interneuron-rich neural progenitor cells at the site of injury can promote anatomical repair and improve respiratory function following SCI. Transplanted neural precursor cells survive, proliferate and become integrated with injured host spinal cord, contributing to repair of respiratory pathways. The experiments proposed here build upon our extensive experience with the phrenic motor system, to test a novel strategy for transplanting refined interneuronal precursors that are associated with phrenic function. Using a clinically relevant contusion model of cervical SCI, we will test whether transplanted neural progenitors can anatomically and functionally integrate with this phrenic system, and promote consistent, lasting recovery of diaphragm. Not only will these experiments test an innovative and promising treatment approach, but they will significantly improve our understanding of the therapeutic potential of a wide range of neuronal transplantation approaches, including many of the stem cell therapies currently being tested experimentally and clinically.
While it has long been thought that spinal cord injuries resulted in permanent paralysis, research has shown that a small amount of recovery ? called plasticity - can occur naturally as the injured spinal cord attempts to rebuild itself. Although this very limited of recovery is reliant on tissues spared by the injury, treatments that promote repair and strengthen plasticity ? like cell transplantation ? will likely lead to the best therapeutic outcomes. Accordingly, the present research program will test whether transplanting refined populations of healthy neurons can provide the building blocks to form new neuronal pathways capable of enhancing plasticity and improving recovery.
