Investigating a cell replacement therapy in the inner ear

Abstract: The mammalian auditory system is sensitive to genetic disorders, aging and injuries caused by overstimulation, ototoxic drugs and viral infections. Since the sensory epithelium (the organ of Corti) and the spiral ganglion neurons (SGNs) in adult mammalian do not regenerate spontaneously when they are damaged, a cell substitution strategy was proposed to compensate the function of the degenerated SGNs. The current study investigated different aspects of cell transplantations in order to test the feasibility of a cell therapy approach in the adult auditory system. Transplanted cells, including embryonic neuronal tissue (mouse embryonic dorsal root ganglion neurons, DRGs) and stem cells (adult neural stem cells, NSCs; embryonic stem cells, ES cells) were found to survive for up to ten weeks in the adult auditory system following transplantation. Supplementing exogenous neurotrophic factors significantly enhanced the survival of DRG neurons. Similarly, ES cell survival was remarkably enhanced by cografting embryonic neuronal tissue. Further research was focused on identifying possible interactions between implanted cells and the host SGNs. The results showed that neurite projections were formed by implanted cells and seemed to contact the host SGNs. The supplement of exogenous nerve growth factor (NGF), chronic electrical stimulation or embryonic neuronal cograft promoted neurite formation. The implanted cells were observed to migrate through the bony modiolus to reach the SGN region in Rosenthal s canal. When tissue was transplanted along the auditory nerve (N. VIII), DRG neurons were found to migrate centrally to the internal meatus while ES cells migrated even further centrally and reached the cochlear nucleus in the brain stem. The results suggest that implanted cells have the potential to structurally integrate with the host auditory system, or even have the capability to replace degenerated SGNs and form connections between the peripheral auditory structures and the central nervous system. Neuronal differentiation of the transplanted stem cells was also investigated. Adult NSCs did not seem to differentiate into a neuronal fate in a normal inner ear. Interestingly, NSCs differentiated into neuron-like cells when they were transduced with neurogenin2 prior to transplantation. ES cells showed differentiation when cografted with embryonic neuronal tissue. The possible function of implanted cells was evaluated in the DRG model by recording electrically-evoked auditory brain stem responses (EABRs). The results showed that exogenous NGF and/or chronic electrical stimulation enhanced neurite outgrowth from the DRG neurons. However, this did not translate to a functional change as measured by EABR. In conclusion, the survival, neurite formation, migration and differentiation of cells implanted into the adult inner ear suggest that a cell replacement approach may provide an alternative for the development of an effective new treatment for hearing loss.