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Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti.

ABSTRACT: Hearing loss in mammals is irreversible because cochlear neurons and hair cells do not regenerate. To determine whether we could replace neurons lost to primary neuronal degeneration, we injected EYFP-expressing embryonic stem cell-derived mouse neural progenitor cells into the cochlear nerve trunk in immunosuppressed animals 1 week after destroying the cochlear nerve (spiral ganglion) cells while leaving hair cells intact by ouabain application to the round window at the base of the cochlea in gerbils. At 3 days post transplantation, small grafts were seen that expressed endogenous EYFP and could be immunolabeled for neuron-specific markers. Twelve days after transplantation, the grafts had neurons that extended processes from the nerve core toward the denervated organ of Corti. By 64-98 days, the grafts had sent out abundant processes that occupied a significant portion of the space formerly occupied by the cochlear nerve. The neurites grew in fasciculating bundles projecting through Rosenthal's canal, the former site of spiral ganglion cells, into the osseous spiral lamina and ultimately into the organ of Corti, where they contacted hair cells. Neuronal counts showed a significant increase in neuronal processes near the sensory epithelium, compared to animals that were denervated without subsequent stem cell transplantation. The regeneration of these neurons shows that neurons differentiated from stem cells have the capacity to grow to a specific target in an animal model of neuronal degeneration.

SUBMITTER: Corrales CE

PROVIDER: S-EPMC2040047 | biostudies-other | 2006 Nov

REPOSITORIES: biostudies-other

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Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti.

Corrales C Eduardo CE Pan Luying L Li Huawei H Liberman M Charles MC Heller Stefan S Edge Albert S B AS

Journal of neurobiology 20061101 13

Hearing loss in mammals is irreversible because cochlear neurons and hair cells do not regenerate. To determine whether we could replace neurons lost to primary neuronal degeneration, we injected EYFP-expressing embryonic stem cell-derived mouse neural progenitor cells into the cochlear nerve trunk in immunosuppressed animals 1 week after destroying the cochlear nerve (spiral ganglion) cells while leaving hair cells intact by ouabain application to the round window at the base of the cochlea in ...[more]

PMID: 17013931

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Project description:UnlabelledThe exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in Tecta(C1509G/C1509G) mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification.Significance statementOuter hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Project description:ObjectivesThis study aimed to compare the effects of increasing the interphase gap (IPG) on the neural response of the electrically stimulated cochlear nerve (CN) between children with CN deficiency (CND) and children with normal-sized CNs.DesignStudy participants included 30 children with CND and 30 children with normal-sized CNs. All subjects were implanted with a Cochlear Nucleus device with the internal electrode array 24RE[CA] in the test ear. The stimulus was a charge-balanced, cathodic leading, biphasic pulse with a pulse-phase duration of 50 μsec. For each subject, the electrically evoked compound action potential (eCAP) input/output (I/O) function was measured for 6 IPGs (i.e., 7, 14, 21, 28, 35, and 42 μsec) at 3 electrode locations across the electrode array. For each subject and each testing electrode, the highest stimulation used to measure the eCAP I/O function was the maximum comfortable level measured with an IPG of 42 μsec. Dependent variables (DVs) were the maximum eCAP amplitude, the eCAP threshold, and the slope of the eCAP I/O function estimated using both linear and sigmoidal regression functions. For each DV, the size of the IPG effect was defined as the proportional change relative to the result measured for the 7 μsec IPG at the basal electrode location. Generalized linear mixed effect models with subject group, electrode location, and IPG duration as the fixed effects and subject as the random effect were used to compare these DVs and the size of the IPG effect on these DVs.ResultsChildren with CND showed smaller maximum eCAP amplitudes, higher eCAP thresholds, and smaller slopes of eCAP I/O function estimated using either linear or sigmoidal regression function than children with normal-sized CNs. Increasing the IPG duration resulted in larger maximum eCAP amplitudes, lower eCAP thresholds and larger slopes of eCAP I/O function estimated using sigmoidal regression function at all three electrode locations in both study groups. Compared with children with normal-sized CNs, children with CND showed larger IPG effects on both the maximum eCAP amplitude and the slope of the eCAP I/O function estimated using either linear or sigmoidal regression function, and a smaller IPG effect on the eCAP threshold than those measured in children with normal-sized CNs.ConclusionsIncreasing the IPG increases responsiveness of the electrically stimulated CN in both children with CND and children with normal-sized CNs. The maximum eCAP amplitude and the slope of the eCAP I/O function measured in human listeners with poorer CN survival are more sensitive to changes in the IPG. In contrast, the eCAP threshold in listeners with poorer CN survival is less sensitive to increases in the IPG. Further studies are warranted to identify the best parameters of eCAP results for predicting CN survival before this eCAP testing paradigm can be used as a clinical tool for evaluating neural health for individual cochlear implant patients.

Dataset Information

Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti.

Publications

Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti.

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