Restoration of auditory evoked responses by human ES-cell-derived otic progenitors

Abstract

Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of a particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells 1, is responsible for a substantial proportion of patients with hearing impairment 2. While the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss since poor innervation limits the prospective performance of an implant 3. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here, we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory evoked response (ABR) thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

“…The ABR results imply that cells transplanted to the nerve surface form synapses both with hair cells and with neurons in the cochlear nuclei in the hindbrain. Evidence for such connections has been shown previously in a subacute model of cell therapy in the auditory system (25). We observed bundles of neurites expressing eGFP in Rosenthal's canal to the habenula perforata (HP, foramina nervosa; Fig.…”

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

“…Finally, other strategies for hearing restoration involve generation of hair cells in vitro from embryonic stem cells or induced pluripotent stem cells followed by reintroduction into the damaged ear. Some of these already rely on manipulation of FGF signaling to promote otic progenitor production (Oshima et al 2010;Chen et al 2012;Koehler et al 2013), but further consideration of FGF signaling levels at later stages of differentiation might be helpful in producing immature support cell progenitors that could be transplanted and then induced to differentiate in situ into hair cells.…”

Ouabain-Induced Cochlear Nerve Degeneration: Synaptic Loss and Plasticity in a Mouse Model of Auditory Neuropathy

“…This neuropathic model has generated significant interest, mainly because of its utility in experiments designed to test the ability of transplanted neural progenitors to survive, grow, and re-innervate a denervated organ of Corti (Corrales et al, 2006;Lang et al, 2008;Chen et al, 2012). Such experiments could pave the way for cell-based therapies for auditory neuropathy, i.e., human hearing loss characterized by primary neural degeneration in the cochlea (Starr et al, 1996).…”