Challenges for stem cells to functionally repair the damaged auditory nerve

Abstract

Introduction: In the auditory system, a specialized subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the brainstem after the loss of hair cells. This neural prosthesis therefore depends on a residual population of functional neurons in order to function effectively.

Areas covered: In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, the benefits derived from a cochlear implant may be minimal. One way in which to restore function to the auditory nerve is to replace these lost neurons using differentiated stem cells, thus re-establishing the neural circuit required for cochlear implant function. Such a therapy relies on producing an appropriate population of electrophysiologically functional neurons from stem cells, and on these cells integrating and reconnecting in an appropriate manner in the deaf cochlea.

Expert opinion: Here we review progress in the field to date, including some of the key functional features that stem cell-derived neurons would need to possess and how these might be enhanced using electrical stimulation from a cochlear implant.

Figure 1

Histological images illustrate the basic anatomy of the normal hearing mammalian (rat) cochlea. A) Transverse section through the mid-modiolar region of the cochlea, illustrating the fluid-filled turns surrounding the central modiolus and entry of the auditory nerve. B) Higher magnification image of a single turn (inset from A), illustrating in more detail the three fluid-filled compartments: scala vestibuli (SV), scala media (SM) and scala tympani (ST). Note that the cochlear implant is inserted directly into the ST to provide electrical stimulation to the auditory neurons, the cell bodies of which reside within Rosenthal’s canal (RC; circled). These neurons extend a peripheral process toward the hair cells (arrows), which are located within the organ of Corti (boxed region), and a central process toward the brainstem. The central processes coalesce to make-up the auditory nerve.

Figure 2

A comparison of neural activity in primary auditory neurons and human embryonic stem cell-derived neurons. Two examples each of cultured primary auditory neurons (A–B) and stem cell-derived neurons (C–D) displaying a rapidly-adapting firing pattern in response to sustained membrane depolarisation. Firing patterns observed in response to pulse trains (20–200Hz) demonstrate differences in the ability of each neuron to follow higher rates of stimulation (asterisks denote stimulus artefact). E) Action potentials fired by auditory neurons (grey) have shorter latency and are briefer than those displayed by stem cell-derived neurons (black). Voltage-clamp recordings in stem cell-derived neurons display sustained outward potassium currents evoked by membrane depolarisation (F–G) and fast inward tetrodotoxin-sensitive sodium current (H).