Transplants of human embryonic stem-cell (hESC)-derived otic progenitor cells have been shown to at least partially restore hearing in gerbils with chemically induced deafness. The achievement, by a team at the University of Sheffield in the U.K., involved the use of defined medium and specific fibroblast growth factors to prompt hESCs to develop into progenitor cells that were capable of differentiating in vitro into both hair-cell-like cells and auditory neurons that displayed electrophysiological properties. When these otic neuroprogenitors were transplanted into a gerbil model of auditory neuropathy, the cells engrafted, differentiated, and improved auditory responses in the treated animals. The gerbils’ initial deafness was caused by treating their ears with ouabain, which kills off spiral ganglion neurons (SGNs) but preserves the hair cells.
Reporting in Nature, Marcelo N. Rivolta, Ph.D., and colleagues say the ability to reinstate auditory neuron functionality could pave the way for a future cell-based treatment for auditory neuropathies in humans. “It may also, in combination with a cochlear implant, offer a therapeutic solution to a wider range of patients that currently remain without viable treatment,” they conclude.
Deafness results primarily from the loss of the sensory hair cells and their associated SGNs, the investigators explain. Of all the forms of deafness, auditory neuropathy is responsible for a substantial proportion of patients with hearing impairment, and is defined primarily by damage to the SGNs, rather than the hair cells. Unfortunately, while loss of hair cells can be addressed partially by a cochlear implant, there isn’t any routine treatment available for sensory neuron loss, as poor innervation limits the prospective performance of an implant.
Attempts to derive hair-cell-like cells and sensory neurons from mouse stem populations have had limited success to date. The resulting cell types may engraft, but they don’t appear to function. Conversely, neuroprogenitors isolated from mature human cochleae display only limited proliferative and differentiation potential. The Sheffield researchers recently succeeded in isolating bipotent stem cells (human fetal auditory stem cells, hFASCs) from human fetal cochlea tissue that could differentiate into hair-cell-like cells and neurons, but the team found that the hFASCs don’t cope with prolonged expansion in vitro, and rapidly undergo replicative senescence.
The successful generation of otic progenitors from hESCs could thus present a real starting point for the development of cell therapies for neuropathies characterized by loss of SGNs, the team reports. “Our developmentally informed protocol produced hESC-derived auditory hair cells and neurons that closely resembled phenotypes obtained from hFASCs, providing validation of their cochlear characteristics.” The investigators report their protocol and in vivo studies in a paper titled “Restoration of auditory evoked responses by human ES-cell-derived otic progenitors.”