scholarly journals Virus-infection in cochlear supporting cells induces audiosensory receptor hair cell death by TRAIL-induced necroptosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260443
Author(s):  
Yushi Hayashi ◽  
Hidenori Suzuki ◽  
Wataru Nakajima ◽  
Ikuno Uehara ◽  
Atsuko Tanimura ◽  
...  
Keyword(s):  
Hair Cells ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Sensory Epithelium ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Receptor Cells ◽  
Macrophage Depletion ◽  
Cochlear Supporting Cells ◽  
Necrosis Factor

Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker’s organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

scholarly journals Generation of Cochlear Hair Cells from Sox2 Positive Supporting Cells via DNA Demethylation

2020 ◽  
Vol 21 (22) ◽  
pp. 8649
Author(s):  
Xin Deng ◽  
Zhengqing Hu
Keyword(s):  
Transgenic Mice ◽  
Inner Ear ◽  
Hair Cells ◽  
Dna Methyltransferase ◽  
Dna Demethylation ◽  
Egfp Expression ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Auditory Hair Cells ◽  
Adult Mice

Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5–7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice.

scholarly journals LIN28B/let-7control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

2020 ◽  
Vol 117 (36) ◽  
pp. 22225-22236
Author(s):  
Xiao-Jun Li ◽  
Angelika Doetzlhofer
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Rna Binding ◽  
Mammalian Target Of Rapamycin ◽  
Cell Loss ◽  
Supporting Cell ◽  
Dependent Manner ◽  
Cell Plasticity ◽  
Supporting Cells ◽  
Cochlear Hair Cells

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNAlet-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

scholarly journals Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sung-Ho Huh ◽  
Mark E Warchol ◽  
David M Ornitz
Keyword(s):  
Growth Factors ◽  
Hair Cells ◽  
Fibroblast Growth Factors ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Feedback Mechanism ◽  
Outer Hair Cells ◽  
Fibroblast Growth ◽  
Supporting Cells ◽  
Fgf Receptor

The sensory and supporting cells (SCs) of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and SCs, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea.

scholarly journals Aquaporin-6 Expression in the Cochlear Sensory Epithelium Is Downregulated by Salicylates

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Paola Perin ◽  
Simona Tritto ◽  
Laura Botta ◽  
Jacopo Maria Fontana ◽  
Giulia Gastaldi ◽  
...  
Keyword(s):  
Inner Ear ◽  
Expression Pattern ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Rt Pcr ◽  
Supporting Cells ◽  
Sensory Epithelia ◽  
Mechanical Compliance

We characterize the expression pattern of aquaporin-6 in the mouse inner ear by RT-PCR and immunohistochemistry. Our data show that in the inner ear aquaporin-6 is expressed, in both vestibular and acoustic sensory epithelia, by the supporting cells directly contacting hair cells. In particular, in the Organ of Corti, expression was strongest in Deiters' cells, which provide both a mechanical link between outer hair cells (OHCs) and the Organ of Corti, and an entry point for ion recycle pathways. Since aquaporin-6 is permeable to both water and anions, these results suggest its possible involvement in regulating OHC motility, directly through modulation of water and chloride flow or by changing mechanical compliance in Deiters' cells. In further support of this role, treating mice with salicylates, which impair OHC electromotility, dramatically reduced aquaporin-6 expression in the inner ear epithelia but not in control tissues, suggesting a role for this protein in modulating OHCs' responses.

scholarly journals Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

2019 ◽  
Author(s):  
Travis A. Babola ◽  
Calvin J. Kersbergen ◽  
Han Chin Wang ◽  
Dwight E. Bergles
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Extracellular Space ◽  
Molecular Mechanisms ◽  
Purinergic Signaling ◽  
Burst Firing ◽  
Supporting Cells ◽  
Cell Excitability ◽  
Sensory Pathways ◽  
Cochlear Supporting Cells

AbstractNeurons in developing sensory pathways exhibit spontaneous bursts of electrical activity that are critical for survival, maturation and circuit refinement. In the auditory system, intrinsically generated activity arises within the cochlea, but the molecular mechanisms that initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 activation triggers K+ efflux and depolarization of hair cells, as well as osmotic shrinkage of supporting cells that dramatically increased the extracellular space and speed of K+ redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal burst firing by reducing K+ release, but unexpectedly enhanced their tonic firing, as water resorption by supporting cells reduced the extracellular space, slowing K+ clearance. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.

scholarly journals Hearing Loss in Neurological Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Siyu Li ◽  
Cheng Cheng ◽  
Ling Lu ◽  
Xiaofeng Ma ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Relevant Literature ◽  
Autism Spectrum ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Wide Range ◽  
Histological Characteristics

Sensorineural hearing loss (SNHL) affects approximately 466 million people worldwide, which is projected to reach 900 million by 2050. Its histological characteristics are lesions in cochlear hair cells, supporting cells, and auditory nerve endings. Neurological disorders cover a wide range of diseases affecting the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), autism spectrum disorder (ASD), etc. Many studies have revealed that neurological disorders manifest with hearing loss, in addition to typical nervous symptoms. The prevalence, manifestations, and neuropathological mechanisms underlying vary among different diseases. In this review, we discuss the relevant literature, from clinical trials to research mice models, to provide an overview of auditory dysfunctions in the most common neurological disorders, particularly those associated with hearing loss, and to explain their underlying pathological and molecular mechanisms.

Distribution of microtubules and microfilaments in developing vestibular sensory epithelium of mouse otocysts grown in vitro

1975 ◽  
Vol 17 (1) ◽  
pp. 171-189
Author(s):  
P. Heywood ◽  
T.R. Van de Water ◽  
D.A. Hilding ◽  
R.J. Ruben
Keyword(s):  
Hair Cells ◽  
Longitudinal Axis ◽  
Ventral Surface ◽  
Sensory Epithelium ◽  
Supporting Cells ◽  
Mitotic Apparatus ◽  
In Vitro Development ◽  
Vitro Development

Otocysts explanted from 12th-gestation-day mice and maintained in organ culture under went a series of developmental changes which paralleled those that occurred in vivo and which resulted in the formation of a sensory epithelium of the vestibular type. At the time of explantation presumptive vestibular sensory epithelium consisted of cells that were undifferentiated, pseudostratified and rapidly proliferating. The only microtubules present were those of the mitotic apparatus. After 4 days of in vitro development cells comprising the presumptive vestibular sensory epithelium were less pseudostratified and more elongate; their nuclei had assumed a basal orientation and there was a clear maginal velum. Longitudinally oriented cytoplasmic microtubules were present at the apices of some cells; they were often grouped around a centriole which may have served as a nucleation centre for their assembly. After 7 days of in vitro development mitosis had ceased and supporting cells had innervated hair cells were present: both types of cells were always longer than they were broad and were often highly asymmetrical. Hair cells were flask- or columnar-shaped, with a nucleus situated in the basal third of the cell. Most mitochondria in hair cells were located in the apical third of the cell. The same distribution of mitochondria and nuclei was evident in supporting cells. Microtubules occurred throughout the length of the supporting cell and were always parallel to its longitudinal axis. In hair cells microtubules were more frequent than in supporting cells: the majority were parallel to the longitudinal axis of the cell but there were two exceptions. First, at the apex of hair cells some microtubules were oriented transversely and diagnonally: these were probably involved in the development and maintenance of the constricted apex of these cells. Secondly, microtubules appeared to be randomly arranged in the narrow region of the cytoplasm between the ventral surface of the nucleus and the base of the hair cells. Microfilaments were confined to the basal third of hair cells where their orientation paralleled that of microtubules. The possible functions of microtubules and microfilaments in the development of hair cells and supporting cells of the mouse vestibular epithelium are discussed.

Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells

Nature ◽  
2006 ◽  
Vol 441 (7096) ◽  
pp. 984-987 ◽  
Author(s):  
Patricia M. White ◽  
Angelika Doetzlhofer ◽  
Yun Shain Lee ◽  
Andrew K. Groves ◽  
Neil Segil
Keyword(s):  
Hair Cells ◽  
Supporting Cells ◽  
Cochlear Supporting Cells

Localization of Glucocorticoid Receptors in the Murine Inner Ear

2002 ◽  
Vol 111 (12) ◽  
pp. 1133-1138 ◽  
Author(s):  
Toshiki Shimazaki ◽  
Masashi Suzuki ◽  
Issei Ichimiya ◽  
Goro Mogi
Keyword(s):  
Inner Ear ◽  
Glucocorticoid Receptors ◽  
Spiral Ligament ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Sensory Epithelia ◽  
Vestibular Sensory Epithelia ◽  
Cochlear Supporting Cells ◽  
Spiral Ganglia

We performed an immunohistochemical investigation of the distribution of glucocorticoid receptors (GRs) in the murine inner ear and found that GRs were expressed extensively, but with various degrees of immunoreactivity in different regions. We observed the strongest GR expression in the type III fibrocytes of the spiral ligament. Although the immunoreactivity of the cochlear hair cells and of the vestibular sensory epithelia was weak, the neighboring cochlear supporting cells and the subepithelial regions of the vestibular sensory epithelia were immunostained. Staining for GRs was also positive in the spiral ganglia and vestibular ganglia, as well as in the endolymphatic sac. The role of GRs in the inner ear is discussed.

scholarly journals Cochlear supporting cells function as macrophage-like cells and protect audiosensory receptor hair cells from pathogens

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yushi Hayashi ◽  
Hidenori Suzuki ◽  
Wataru Nakajima ◽  
Ikuno Uehara ◽  
Atsuko Tanimura ◽  
...  
Keyword(s):  
Hair Cells ◽  
Supporting Cells ◽  
Cochlear Supporting Cells
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