Spike Generators and Cell Signaling in the Human Auditory Nerve: An Ultrastructural, Super-Resolution, and Gene Hybridization Study

Johansson

Rask‐Andersen

et al. 2021

BMC Med

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Background Sensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated. Methods We performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4. Results All proteins were found to be expressed in human cochlear structures. Our findings illustrate cochlear structures that mediate mechano-electric transduction of auditory stimuli, neuronal conductance, and neuronal plasticity to be involved in age-related hearing loss. Conclusions Our results suggest common genetic variation to influence structural resilience to damage as well as cochlear recovery after trauma, which protect against accumulated damage to cochlear structures and the development of hearing loss over time.

Section: Co-staining Of Synaptojanin 2 (Ch) and Matrix Metalloproteinase 2 (Mmp2)contrasting

confidence: 94%

“…The cells of Claudius were not labeled but are located above the cells of Boettcher. Image adapted with permission from Liu et al [117] the cochlea of the common marmoset, Callithrix jacchus [32]. We are also able to report EYA4 expression in the wall of the inner spiral sulcus.…”

Section: Eyes Absent Homolog 4 (Eya4)supporting

confidence: 52%

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

Johansson

Rask‐Andersen

et al. 2021

BMC Med

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“…The technique that we used for sampling human tissue was previously described ( 18 ). Specimens were from patients suffering from life-threatening posterior cranial fossa meningioma compressing the brain stem ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

Distribution of Immune Cells Including Macrophages in the Human Cochlea

Danckwardt-Lillieström

Schrott‐Fischer

et al. 2021

Front. Neurol.

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Background: The human cochlea was earlier believed to lack capacity to mount specific immune responses. Recent studies established that the human cochlea holds macrophages. The cells appear to surveil, dispose of, and restore wasted cells to maintain tissue integrity. Macrophage activities are believed to be the central elements in immune responses and could swiftly defuse invading microbes that enter via adjacent infection-prone areas. This review updates recent human studies in light of the current literature and adds information about chemokine gene expression.Materials and Methods: We analyzed surgically obtained human tissue using immunohistochemistry, confocal microscopy, and multichannel super-resolution structured illumination microscopy. The samples were considered representative of steady-state conditions. Antibodies against the ionized calcium-binding adaptor molecule 1 were used to identify the macrophages. CD68 and CD11b, and the major histocompatibility complex type II (MHCII) and CD4 and CD8 were analyzed. The RNAscope technique was used for fractalkine gene localization.Results: Many macrophages were found around blood vessels in the stria vascularis but not CD4 and CD8 lymphocytes. Amoeboid macrophages were identified in the spiral ganglion with surveilling “antennae” projecting against targeted cells. Synapse-like contacts were seen on spiral ganglion cell bodies richly expressing single CXC3CL gene transcripts. Branching neurite-like processes extended along central and peripheral axons. Active macrophages were occasionally found near degenerating hair cells. Some macrophage-interacting T lymphocytes were observed between the scala tympani wall and Rosenthal's canal. CD4 and CD8 cells were not found in the organ of Corti.Conclusions: The results indicate that the human cochlea is equipped with macrophages and potentially lymphocytes, suggesting both an innate and adaptive immune capacity. A rich expression of fractalkine gene transcripts in spiral ganglion neurons suggest an essential role for auditory nerve protection, as has been demonstrated experimentally. The findings provide further information on the important role of the immune machinery present in the human inner ear and its potential to carry adverse immune reactions, including cytotoxic and foreign body responses. The results can be used to form a rationale for therapies aiming to modulate these immune activities.

“…Studies have shown that morphological and molecular divergences also exist among species ( Liu et al, 2009 ; Liu W. et al, 2021 ). Thus far, broad investigations of gene distribution and expression profiles in the human cochlea have not been presented.…”

Section: Introductionmentioning

confidence: 99%

“…NKA is a key ion transporter which maintains the EP and has been investigated in different species by several authors with somewhat different results ( Kuijpers and Bonting, 1969 ; Mees, 1983 ; Schulte and Adams, 1989 ; Ichimiya et al, 1994 ; Schulte and Steel, 1994 ; Keithley et al, 1995 ; Peters et al, 2001 ; Weber et al, 2001 ; McLean et al, 2009 ; Liu et al, 2019 ; Stephenson et al, 2021 ). Studies of NKA expression were performed previously in the human cochlea ( Weber et al, 2001 ; Liu et al, 2019 ; Liu W. et al, 2021 ; Stephenson et al, 2021 ). NKA is extensively expressed in human spiral ganglion somata, supporting its role in the relay and repolarization after spike activation ( Pivovarov et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Na/K-ATPase Gene Expression in the Human Cochlea: A Study Using mRNA in situ Hybridization and Super-Resolution Structured Illumination Microscopy

Rask‐Andersen

2022

Front. Mol. Neurosci.

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BackgroundThe pervasive Na/K-ATPase pump is highly expressed in the human cochlea and is involved in the generation of the endocochlear potential as well as auditory nerve signaling and relay. Its distribution, molecular organization and gene regulation are essential to establish to better understand inner ear function and disease. Here, we analyzed the expression and distribution of the ATP1A1, ATP1B1, and ATP1A3 gene transcripts encoding the Na/K-ATPase α1, α3, and β1 isoforms in different domains of the human cochlea using RNA in situ hybridization.Materials and MethodsArchival paraformaldehyde-fixed sections derived from surgically obtained human cochleae were used to label single mRNA gene transcripts using the highly sensitive multiplex RNAscope® technique. Localization of gene transcripts was performed by super-resolution structured illumination microscopy (SR-SIM) using fluorescent-tagged probes. GJB6 encoding of the protein connexin30 served as an additional control.ResultsSingle mRNA gene transcripts were seen as brightly stained puncta. Positive and negative controls verified the specificity of the labeling. ATP1A1 and ATP1B1 gene transcripts were demonstrated in the organ of Corti, including the hair and supporting cells. In the stria vascularis, these transcripts were solely expressed in the marginal cells. A large number of ATP1B1 gene transcripts were found in the spiral ganglion cell soma, outer sulcus, root cells, and type II fibrocytes. The ATP1B1 and ATP1A3 gene transcripts were rarely detected in axons.DiscussionSurgically obtained inner ear tissue can be used to identify single mRNA gene transcripts using high-resolution fluorescence microscopy after prompt formaldehyde fixation and chelate decalcification. A large number of Na/K-ATPase gene transcripts were localized in selected areas of the cochlear wall epithelium, fibrocyte networks, and spiral ganglion, confirming the enzyme’s essential role for human cochlear function.