Auditory Stem Cell Transplantation and Cochlear Implants in Animal Models of Deafness

Hearing loss is a main public health issue, with more than 250 million people affected worldwide. The vast majority of these cases are produced by the damage of two critical cells of the hearing pathway, the sensory hair cells and the auditory neurons located in the cochlea. Hair cells can ?sense? sound by detecting small vibrations through the movement of the tiny ?hairs? located at their top. This movement is translated into electrical signals that are sent to the auditory neurons, which in turn take the information to the brain. While birds have the ability to regenerate and replace hair cells, mammals in general and humans in particular have lost this ability. Sensory hair cells and neurons are only produced in the womb during development, making their loss permanent and deafness irreversible. At the moment, no medical treatment is available for the condition. However, in severe cases, the function of the lost hair cells can be replaced by a prosthetic device, the cochlear implant. The cochlear implant, however, can only work provided the auditory neurons are preserved. In many patients this is not the case and cochlear implantation is not possible. Even worst, since it is difficult to judge the quality of the neurons beforehand, some patients are implanted only to have their hopes shattered by a poor performance and little or no recovery of hearing. In this project, we want to explore if, by using stem cells, we could replace the damaged neurons and enhance the efficacy and applicability of cochlear implants in the treatment of deafness. Our laboratory has already succesfully isolated populations of human stem cells that have the capacity to produce sensory neurons in a test tube. Now, we want to use them toghether with cochlear implants, to treat animals that have a deafness similar to that which will lead to a cochlear implant failure in humans. We want to see if the transplanted cells will establish connections with the electrical electrodes and eventually, produce a functional recovery. If succesful, these findings could pave the way to offer a solution to thousands of patients that cannot be helped today with conventional cochlear implants.

Deafness is a main public health issue, with more than 250 million affected worldwide. The vast majority of these cases (90%) are produced by the damage of the sensory hair cells and auditory neurons, the two initial cells of the hearing pathway located in the cochlea. In mammals, these cells are only produced in utero during development, making their loss permanent and deafness irreversible. No medical treatment is currently available for the condition. However, if the auditory neurons are preserved the function of the hair cells can be replaced by a prosthetic device, the cochlear implant (CI). Our laboratory has pursued during the last few years, the identification and generation of human auditory stem cells, with the aim of developing a stem cell?based therapy for deafness. We have successfully isolated auditory stem cells form the human fetal cochlea (hFASCs), the first of their kind from humans. We have also developed protocols to coerce human embryonic stem cells into otic phenotypes by using signals mimicking the normal development in vivo. The differentiated neurons and hair cell-like cells obtained from both systems display functional properties resembling those produced in vivo. We are currently transplanting hESC-derived otic neuroprogenitors into a model of neuropathic deafness. These cells have grafted and survive for at least 12 weeks, differentiate into TUJ1+ neurons and extend projections. More importantly, preliminary measurements of hearing function using Auditory Brainstem Responses (ABRs) show a significant recovery of hearing. The aim of the present application is to combine the use of stem cells and CI in profoundly deafened animal models. Our objectives include the assessment of neuronal survival in the presence of cochlear electrodes, the role of electrical stimulation in differentiation and survival, and obviously the regeneration of auditory function as measured by ABRs. For this purpose we are collaborating with Prof O?Donohue, director of one of the leading clinical CI programmes in the country as well as with the implant developing company, Cochlear. The challenges faced by stem cell technologies to deliver a realistic clinical application in general are still substantial. However, we believe that by replacing the hair cells with a CI and supplementing sensory neurons with stem cells we could generate a holistic approach that could significantly enhance the therapeutic applications of current CI to a wider number of patients, making a stem cell-based therapy for deafness a real possibility in a not too distant future.