Abstract
The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration.
Highlights
The use of cochlear implants (CIs) is the standard of care for patients with severe-to-profound sensorineural hearing loss (SNHL) [1], though users frequently note poor speech perception in noisy environments and often find it challenging to appreciate music [2]
Despite recent encouraging progress in regenerating spiral ganglion neurons (SGNs) in animal models by transplanting cells derived from human embryonic stem cells into the inner ear [4,5], clinical translation requires increasing the efficiency of otic neural progenitor cell (ONP) production, neuronal differentiation, preferential placement of ONPs, and long-term in vivo survival
Our findings suggest that combining stem cell transplantation with injection of self-assembling peptide amphiphile (PA) gels to create a supportive cell niche may improve the success of stem cell-based approaches to auditory nerve regeneration
Summary
The use of cochlear implants (CIs) is the standard of care for patients with severe-to-profound sensorineural hearing loss (SNHL) [1], though users frequently note poor speech perception in noisy environments and often find it challenging to appreciate music [2]. One promising treatment strategy involves the repopulation of spiral ganglion neurons (SGNs) in the cochlea, which undergo irreversible retrograde trans-synaptic degeneration in this patient population [3]. Despite recent encouraging progress in regenerating SGNs in animal models by transplanting cells derived from human embryonic stem cells (hESCs) into the inner ear [4,5], clinical translation requires increasing the efficiency of otic neural progenitor cell (ONP) production, neuronal differentiation, preferential placement of ONPs, and long-term in vivo survival. We described a protocol for controlled and efficient creation of hESC-derived ONP populations [8]. We focus on a subsequent step: creating a supportive extracellular niche in the inner ear in vivo that supports survival and adequate neuronal differentiation of transplanted hESCderived ONPs
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