The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234926 | GEO | 2024/01/18
REPOSITORIES: GEO
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Project description:The stria vascularis (SV) is an intricate non-sensory structure composed of multiple cell layers of different origins in the mammalian cochlea. It generates and maintains the endolymph, and therefore is essential for hearing functions. Here, using single cell transcriptomics and transgenic mouse models, we discover that the Shh receptor Ptch1 is required for marginal cell (MC, the epithelial cell layer of SV) differentiation and SV development. During cochlear development, MC differentiation gradually proceeds from cochlear base to apex, resembling the spatiotemporal differentiation pattern of sensory hair cells. Inactivation of Ptch1 leads to an impaired MC differentiation through elevated Gli2 levels, and inhibition of Gli2/Shh signaling activity is a prerequisite for MC differentiation. Single cell transcriptome analyses reveal that MCs are specified as early as E14. Moreover, in the absence of Ptch1, MC precursors are maintained in the progenitor state and differentiation is blocked consequently.
2024-04-03 | GSE217373 | GEO
Project description:The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss
| PRJNA983754 | ENA
Project description:SLC26A4 mutations can cause a distinctive hearing loss phenotype with sudden drops and fluctuation in patients. Existing Slc26a4 mutant mouse lines have a profound loss of hearing and vestibular function, with severe inner ear malformations that do not model this human phenotype. In this study, we generated Slc26a4-insufficient mice by manipulation of doxycycline administration to a transgenic mouse line in which all Slc26a4 expression was under the control of doxycycline. Doxycycline was administered from conception to embryonic day 17.5, and then it was discontinued. Auditory brainstem response thresholds showed significant fluctuation of hearing loss from 1 through 3months of age. The endocochlear potential, which is required for inner ear sensory cell function, correlated with auditory brainstem response thresholds. We observed degeneration of stria vascularis intermediate cells, the cells that generate the endocochlear potential, but no other abnormalities within the cochlea. We conclude that fluctuations of hearing result from fluctuations of the endocochlear potential and stria vascularis dysfunction in Slc26a4-insufficient mouse ears. This model can now be used to test potential interventions to reduce or prevent sudden hearing loss or fluctuation in human patients. Our strategy to generate a hypomorphic mouse model utilizing the tet-on system will be applicable to other diseases in which a hypomorphic allele is needed to model the human phenotype.
| S-EPMC3995827 | biostudies-literature
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging The totoal RNA was extracted from the lateral wall of cochlear duct from CBA/J and C57BL/6J mice at different ages. The expression profile of miRNAs was examined by miR microarray GeneChip.
2014-10-01 | E-GEOD-57782 | biostudies-arrayexpress
Project description:The endocochlear potential (EP) is essential to hearing, because it provides approximately half of the driving force for the mechanoelectrical transduction current in auditory hair cells. The EP is produced by the stria vascularis (SV), a vascularized bilayer epithelium of the cochlea lateral wall. The absence of the gap junction protein connexin30 (Cx30) in Cx30(-/-) mice results in the SV failure to produce an EP, which mainly accounts for the severe congenital hearing impairment of these mice. Here, we show that the SV components of the EP electrogenic machinery and the epithelial barriers limiting the intrastrial fluid space, which are both necessary for the EP production, were preserved in Cx30(-/-) mice. In contrast, the endothelial barrier of the capillaries supplying the SV was disrupted before EP onset. This disruption is expected to result in an intrastrial electric shunt that is sufficient to account for the absence of the EP production. Immunofluorescence analysis of wild-type mice detected Cx30 in the basal and intermediate cells of the SV but not in the endothelial cells of the SV capillaries. Moreover, dye-coupling experiments showed that endothelial cells were not coupled to the SV basal, intermediate, and marginal cells. SV transcriptome analysis revealed a significant down-regulation of betaine homocysteine S-methyltransferase (Bhmt) in the Cx30(-/-) mice, which was restricted to the SV and resulted in a local increase in homocysteine, a known factor of endothelial dysfunction. Disruption of the SV endothelial barrier is a previously undescribed pathogenic process underlying hearing impairment.
| S-EPMC1851033 | biostudies-literature
Project description:Ptch1/Shh signaling control cochlear marginal cell differentiation and stria vascularis formation
| PRJNA898638 | ENA
Project description:BackgroundAge-related hearing loss, known as presbycusis, is the result of auditory system degeneration. Numerous studies have suggested that reactive oxygen species (ROS) and mitochondrial oxidative damage play important roles in the occurrence and progression of aging. The D-galactose (D-gal)-induced aging model is well known and widely utilized in aging research. Our previous studies demonstrate that administration of D-gal causes mitochondrial oxidative damage and causes subsequent dysfunction in the cochlear ribbon synapses, which in turn leads to hearing changes and early stage presbycusis. Stria vascularis (SV) cells are vital for hearing function. However, it is unclear to what extent D-gal induces oxidative damage and apoptosis in the cochlear SV of mice. In addition, the source of the causative ROS in the cochlear SV has not been fully investigated.MethodsIn this study, we investigated ROS generation in the cochlear SV of mice treated with D-gal. Hearing function was measured using the auditory brainstem response (ABR). Immunofluorescence was used to examine apoptosis and oxidative damage. Transmission electron microscopy was also used to investigate the mitochondrial ultrastructure. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Mitochondrial membrane potential (MMP) and ATP were also measured.ResultsWe found that D-gal-treated mice exhibited a significant shift in the mean amplitude and latency of the ABR; a remarkable increase in the levels of NADPH oxidase (NOX-2), Uncoupling protein 2 (UCP2) and cleaved caspase-3 (c-Cas3) was observed, as well as an increase in the number of TUNEL-positive cells were observed in the SV of mice. Both the expression of the DNA oxidative damage biomarker 8-hydroxy-2-deoxyguanosine (8-OHdG) and a commonly occurring mitochondrial DNA deletion were markedly elevated in the SV of mice that had been treated with D-gal to induce aging. Conversely, the ATP level and MMP were significantly reduced in D-gal-induced aging mice. We also found alterations in the mitochondrial ultrastructure in the SV of aging mice, which include swollen and distorted mitochondrial shape, shortened and thickened microvilli, and the accumulation of lysosomes in the SV.ConclusionOur findings suggest that the impairment of cochlear SV during presbycusis may be caused by mitochondrial oxidative damage and subsequent apoptosis.
| S-EPMC10441755 | biostudies-literature
Project description:BackgroundThe stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets.MethodsWe analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways.ResultsThrough the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain.ConclusionOur bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.
| S-EPMC10897997 | biostudies-literature
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging
2014-10-01 | GSE57782 | GEO
Project description:Evaluation of transcriptional changes in the E14.5 cochlear duct epithelium upon tamoxifen-induced loss of Tbx2 in prosensory cells.
2022-11-04 | GSE180500 | GEO