Embryonic Stem Cell-Derived Neurons for Inner Ear Therapy

Abstract

Sensorineural hearing loss is a major public health problem affecting more than 278 million people worldwide. The primary cause of sensorineural hearing loss is loss or damage of sensory hair cells in the organ of Corti. However, approximately 10-15% of cases with profound hearing loss in children are caused by degeneration of the spiral ganglion neurons (SGNs) or neurons in the auditory brainstem. Moreover, SGNs gradually degenerate after the loss of hair cells due to a lack of excitatory stimulation. Since SGNs do not regenerate to any clinically significant extent, novel therapies for their preservation, regeneration or replacement are being heavily sought. Currently, no treatment option is available for peripheral auditory neuropathy. Cell-based therapies offer a strategy to enhance auditory functions in the deaf patient and improve the benefits of cochlear implantation. There are three major areas for potential clinical applications relevant to this approach. First, for patients who have received cochlear implants, generation or preservation of SGNs via cell replacement therapy could significantly improve the quality of their sound perception. Another group of potential recipients who would benefit from cell replacement therapy are patients suffering from acoustic neuroma or neurofibromatosis. These patients generally exhibit significant loss of auditory or vestibular primary neurons with relatively intact sensory hair cells (Kaga et al., 1997; Evans et al., 2000; Sperfeld et al., 2002). Thus, replacing dead or damaged neurons with stem cells could be critical in restoring their hearing or balance sensation. Finally, auditory neurons generated from stem cells could be used in in vitro assays to test the effectiveness and safety of newly developed drugs before clinical trials. Type I SGNs, comprising 95% of all neural populations in the SG, innervate inner hair cells in the organ of Corti and function as the primary auditory afferent neurons (Berglund and Ryugo, 1987; Liberman et al., 1990; Rusznak and Szucs, 2009). These SGNs predominantly express AMPA receptors (mainly GluR2-4) (Niedzielski and Wenthold, 1995; Parks, 2000; Dulon et al., 2006; Chen et al., 2007; Flores-Otero et al., 2007), which bind the neurotransmitter glutamate released from inner hair cells (Fig. 1). This subsequently triggers action potentials that propagate along the nerve fibers to the cochlear nucleus. The majority, if not all, of type I SGNs are glutamatergic and release glutamate from their presynaptic membrane in the cochlear nucleus (Rebillard et al., 2003; Reyes et al., 2008). Expression of AMPA receptors and glutamate transporters thus is the hallmark of mature type I SGNs. During embryonic development, SGNs arise from the otic placode and