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

Wei Chen,1, 2, 4 Nopporn Jongkamonwiwat,1, 2, 3, 4 Leila Abbas,1, 2 Sarah Jacob Eshtan,1, 2 Stuart L. Johnson,2 Stephanie Kuhn,2 Marta Milo,2 Johanna K. Thurlow,1, 2 Peter W. Andrews,1, 2 Walter Marcotti,2 Harry D. Moore1, 2 & Marcelo N. Rivolta1, 2

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 particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells1, is responsible for a substantial proportion of patients with hearing impairment2. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant3. 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 thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.

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