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International Journal of Molecular... May 2024Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting a significant portion of older adults and involving various... (Review)
Review
Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting a significant portion of older adults and involving various interacting mechanisms. Metabolic presbycusis, a type of age-related HL, is characterized by the dysfunction of the stria vascularis, which is crucial for maintaining the endocochlear potential necessary for hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as a key factor in age-related HL. This narrative review integrates past and recent research, bridging findings from animal models and human studies, to examine the contributions of the stria vascularis to age-related HL. It provides a brief overview of the structure and function of the stria vascularis and then examines mechanisms contributing to age-related strial dysfunction, including altered ion transport, changes in pigmentation, inflammatory responses, and vascular atrophy. Importantly, this review outlines the contribution of metabolic mechanisms to age-related HL, highlighting areas for future research. It emphasizes the complex interdependence of metabolic and sensorineural mechanisms in the pathology of age-related HL and highlights the importance of animal models in understanding the underlying mechanisms. The comprehensive and mechanistic investigation of all factors contributing to age-related HL, including cochlear metabolic dysfunction, remains crucial to identifying the underlying mechanisms and developing personalized, protective, and restorative treatments.
Topics: Humans; Stria Vascularis; Animals; Presbycusis; Aging; Cochlea; Hearing Loss
PubMed: 38791427
DOI: 10.3390/ijms25105391 -
Cell Reports Apr 2024A common cause of deafness in humans is dysregulation of the endocochlear potential generated by the stria vascularis (SV). Thus, proper formation of the SV is critical...
A common cause of deafness in humans is dysregulation of the endocochlear potential generated by the stria vascularis (SV). Thus, proper formation of the SV is critical for hearing. Using single-cell transcriptomics and a series of Shh signaling mutants, we discovered that the Shh receptor Patched1 (Ptch1) is essential for marginal cell (MC) differentiation and SV formation. Single-cell RNA sequencing analyses revealed that the cochlear roof epithelium is already specified into discrete domains with distinctive gene expression profiles at embryonic day 14, with Gsc as a marker gene of the MC lineage. Ptch1 deficiency leads to defective specification of MC precursors along the cochlear basal-apical regions. We demonstrated that elevated Gli2 levels impede MC differentiation through sustaining Otx2 expression and maintaining the progenitor state of MC precursors. Our results uncover an early specification of cochlear non-sensory epithelial cells and establish a crucial role of the Ptch1-Gli2 axis in regulating the development of SV.
Topics: Patched-1 Receptor; Cell Differentiation; Animals; Mice; Stria Vascularis; Cochlea; Signal Transduction; Zinc Finger Protein Gli2; Hedgehog Proteins
PubMed: 38602877
DOI: 10.1016/j.celrep.2024.114083 -
AIP Conference Proceedings Feb 2024Two hydrodynamic effects are introduced in the standard transmission-line formalism, the focusing of the pressure and fluid velocity fields near the basilar membrane and...
Two hydrodynamic effects are introduced in the standard transmission-line formalism, the focusing of the pressure and fluid velocity fields near the basilar membrane and the viscous damping at the fluid-basilar membrane interface, which significantly affect the cochlear response in the short-wave region. In this region, in which the wavelength is shorter than the cochlear duct height, only a layer of fluid of order of the wavelength is effectively involved in the traveling wave. This has been interpreted [8] as a reduced fluid contribution to the system inertia in the peak region, which is a viewpoint common to the 3-D FEM solutions. In this paper we propose an alternative approach, from a slightly different physical viewpoint. Invoking the fluid flux conservation along the traveling wave propagation direction, we can derive a rigorous propagation equation for the pressure integrated along the vertical axis. Consequently, the relation between the average pressure and the local pressure [4] at the fluid-BM interface can be written. The local pressure is amplified by a factor dependent on the local wavenumber with respect to the average pressure, a phenomenon we refer to as "fluid focusing", which plays a relevant role in the BM total amplification gain. This interpretation of the hydrodynamic boost to the pressure provides a physical justification to the strategy [10] of fitting the BM admittance with a polynomial containing both a conjugated pole and a zero. In the short-wave region, the sharp gradients of the velocity field yield a second important effect, a damping force on the BM motion, proportional to the local wavenumber, which stabilizes active models and shifts the peak of the response towards the base, with respect to the resonant place. This way, the peaked BM response is not that of a proper resonance, corresponding to a sharp maximum of the admittance, but rather a focusing-driven growth toward the resonant place, which is "aborted" before reaching it by the sharply increasing viscous losses. The large values of the wavenumber that ensure strong focusing are ultimately fueled, against viscosity, by the nonlinear OHC mechanism, hence the otherwise puzzling observation of a wide nonlinear gain dynamics with almost level-independent admittance.
PubMed: 38516506
DOI: 10.1063/5.0189302 -
BMC Genomics Feb 2024The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required...
BACKGROUND
The 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.
METHODS
We 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.
RESULTS
Through 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.
CONCLUSION
Our 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.
Topics: Adult; Humans; Animals; Mice; Stria Vascularis; Single-Cell Gene Expression Analysis; Hearing Loss, Sensorineural; Cochlea; Transcription Factors
PubMed: 38413848
DOI: 10.1186/s12864-024-10122-7 -
Cell Reports Mar 2024Hearing starts, at the cellular level, with mechanoelectrical transduction by sensory hair cells. Sound information is then transmitted via afferent synaptic connections...
Hearing starts, at the cellular level, with mechanoelectrical transduction by sensory hair cells. Sound information is then transmitted via afferent synaptic connections with auditory neurons. Frequency information is encoded by the location of hair cells along the cochlear duct. Loss of hair cells, synapses, or auditory neurons leads to permanent hearing loss in mammals. Birds, in contrast, regenerate auditory hair cells and functionally recover from hearing loss. Here, we characterized regeneration and reinnervation in sisomicin-deafened chickens and found that afferent neurons contact regenerated hair cells at the tips of basal projections. In contrast to development, synaptic specializations are established at these locations distant from the hair cells' bodies. The protrusions then contracted as regenerated hair cells matured and became functional 2 weeks post-deafening. We found that auditory thresholds recovered after 4-5 weeks. We interpret the regeneration-specific synaptic reestablishment as a location-preserving process that might be needed to maintain tonotopic fidelity.
Topics: Animals; Chickens; Hair Cells, Auditory; Hearing; Hearing Loss; Sound; Mammals
PubMed: 38393948
DOI: 10.1016/j.celrep.2024.113822 -
Scientific Reports Feb 2024The stria vascularis (SV) is a stratified epithelium in the lateral wall of the mammalian cochlea, responsible for both endolymphatic ion homeostasis and generation of...
The stria vascularis (SV) is a stratified epithelium in the lateral wall of the mammalian cochlea, responsible for both endolymphatic ion homeostasis and generation of the endocochlear potential (EP) critical for normal hearing. The SV has three layers consisting predominantly of basal, intermediate, and marginal cells. Intermediate and marginal cells form an intricate interdigitated network of cell projections making discrimination of the cells challenging. To enable intermediate cell visualization, we engineered by BAC transgenesis, reporter mouse lines expressing ZsGreen fluorescent protein under the control of Kcnj10 promoter and regulatory sequences. Kcnj10 encodes KCNJ10 protein (also known as Kir4.1 or Kir1.2), an ATP-sensitive inwardly-rectifying potassium channel critical to EP generation, highly expressed in SV intermediate cells. In these transgenic mice, ZsGreen fluorescence mimics Kcnj10 endogenous expression in the cochlea and was detected in the intermediate cells of the SV, in the inner phalangeal cells, Hensen's, Deiters' and pillar cells, in a subset of spiral ganglion neurons, and in glial cells. We show that expression of the transgene in hemizygous mice does not alter auditory function, nor EP. These transgenic Tg(Kcnj10-ZsGreen) mice allow live and fixed tissue visualization of ZsGreen-expressing intermediate cells and will facilitate future studies of stria vascularis cell function.
Topics: Animals; Mice; Stria Vascularis; Potassium Channels, Inwardly Rectifying; Cochlea; Ear, Inner; Mice, Transgenic; Mammals
PubMed: 38321040
DOI: 10.1038/s41598-024-52663-7 -
Scientific Reports Jan 2024Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause...
Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause Waardenburg syndrome and abnormalities of skin and retinal melanocytes, manifested as congenital hearing loss (~ 70%) and hypopigmentation of skin, hair and eyes. However, the underlying mechanism of hearing loss remains unclear. Cochlear melanocytes in the stria vascularis originated from Pax3-traced melanoblasts and Plp1-traced Schwann cell precursors, both of which derive from neural crest cells. Here, using a Pax3-Cre knock-in mouse that allows lineage tracing of Pax3-expressing cells and disruption of Pax3, we found that Pax3 deficiency causes foreshortened cochlea, malformed vestibular apparatus, and neural tube defects. Lineage tracing and in situ hybridization show that Pax3 derivatives contribute to S100, Kir4.1 and Dct melanocytes (intermediate cells) in the developing stria vascularis, all of which are significantly diminished in Pax3 mutant animals. Taken together, these results suggest that Pax3 is required for the development of neural crest cell-derived cochlear melanocytes, whose absence may contribute to congenital hearing loss of Waardenburg syndrome in humans.
Topics: Mice; Animals; Humans; Waardenburg Syndrome; Cochlea; Stria Vascularis; Hearing Loss; Hearing Loss, Sensorineural; Melanocytes; Deafness; PAX3 Transcription Factor
PubMed: 38278860
DOI: 10.1038/s41598-024-52629-9 -
Pakistan Journal of Medical Sciences 2024To analyze the gender, age and side association of cochlear duct length in Pakistani-Asian cochlear implant recipient population based on computed tomography imaging...
OBJECTIVES
To analyze the gender, age and side association of cochlear duct length in Pakistani-Asian cochlear implant recipient population based on computed tomography imaging study.
METHODS
Current study retrospectively studied charts of cases who underwent cochlear implantation at the Department of Otolaryngology & Auditory Implant Centre, Capital Hospital Islamabad, over a period of two years from 1st May 2017 to 30th April 2019. These included 200 cases of both genders and of any age. In addition to basic demographic data, computed tomography findings of the temporal bone were utilized to measure the cochlear duct length. Data was analyzed using SPSS Version 23.
RESULTS
Study revealed a mean Cochlear duct length of 29.935±2.173mm (range: 25.12 to 37.60) with significant (p<0.001) association with gender with longer cochlear duct in males compared to females on right (30.50±2.384 vs. 29.36±1.887) and on left side (30.50±2.236 vs.29.32±1.935). However, no significant difference was noted for side with slightly longer cochlear duct on the right side compared to left (29.95±2.224 vs.29.92±2.171). Also, no significant association with age was noted with p=0.578 & p=0.824 for right and left side respectively.
CONCLUSION
Pakistani population is characterized by a short mean CDL of 29.935±2.173 mm with significant association (p<0.001) with gender with longer cochlear duct length in males; and side with larger CDL on right side. However, no significant association with age was noted.
PubMed: 38196493
DOI: 10.12669/pjms.40.1.7426 -
Annals of Biomedical Engineering Mar 2024Accurate 3D models of the cochlea are useful tools for research in the relationship between the electrode array and nerve fibres. The internal geometry of the cochlear...
Accurate 3D models of the cochlea are useful tools for research in the relationship between the electrode array and nerve fibres. The internal geometry of the cochlear canal plays an important role in understanding and quantifying that relationship. Predicting the location and shapes of the geometry is done by measuring histologic sections and fitting equations that can be used to predict parameters that fully define the geometry. A parameter sensitivity analysis is employed to prove that the size and location of the spiral lamina are the characteristics that most influence current distribution along target nerve fibres. The proposed landmark prediction method more accurately predicts the location of the points defining the spiral lamina in the apical region of the cochlea than methods used in previous modelling attempts. Thus, this technique can be used to generate 2D geometries that can be expanded to 3D models when high-resolution imaging is not available.
Topics: Cochlea; Electrodes; Temporal Bone; Electric Stimulation; Cochlear Implants; Cochlear Implantation
PubMed: 38165632
DOI: 10.1007/s10439-023-03417-5 -
Scientific Reports Dec 2023Estimating insertion depth, cochlear duct length (CDL), and other inner ear parameters is vital to optimizing cochlear implantation outcomes. Most current formulas use...
Estimating insertion depth, cochlear duct length (CDL), and other inner ear parameters is vital to optimizing cochlear implantation outcomes. Most current formulas use only the basal turn dimensions for CDL prediction. In this study, we investigated the importance of the second turn parameters in estimating CDL. Two experienced neuro-otologists blindly used segmentation software to measure (in mm) cochlear parameters, including basal turn diameter (A), basal turn width (B), second-turn diameter (A2), second-turn width (B2), CDL, first-turn length, and second-turn length (STL). These readings were taken from 33 computed tomography (CT) images of temporal bones from anatomically normal ears. We constructed regression models using A, B, A2, and B2 values fitted to CDL, two-turn length, and five-fold cross-validation to ensure model validity. CDL, A value, and STL were longer in males than in females. The mean B2/A2 ratio was 0.91 ± 0.06. Adding A2 and B2 values improved CDL prediction accuracy to 86.11%. Therefore, we propose a new formula for more accurate CDL estimation using A, B, A2, and B2 values. In conclusion, the findings of this study revealed a notable improvement in the prediction of two-turn length (2TL), and CDL by clinically appreciable margins upon adding A2 and B2 values to the prediction formulas.
Topics: Male; Female; Humans; Cochlear Duct; Cochlea; Cochlear Implantation; Tomography, X-Ray Computed; Temporal Bone; Cochlear Implants
PubMed: 38057331
DOI: 10.1038/s41598-023-48641-0