Inner ear supporting cells protect hair cells by secreting HSP70

Strict control of cellular proliferation is required to shape the complex structures of the developing embryo. The organ of Corti, the auditory neuroepithelium of the inner ear in mammals, consists of two types of terminally differentiated mechanosensory hair cells and at least four types of supporting cells arrayed precisely along the length of the spiral cochlea. In mice, the progenitors of greater than 80% of both hair cells and supporting cells undergo their terminal division between embryonic day 13 (E13) and E14. As in humans, these cells persist in a non-proliferative state throughout the adult life of the animal. Here we report that the correct timing of cell cycle withdrawal in the developing organ of Corti requires p27(Kip1), a cyclin-dependent kinase inhibitor that functions as an inhibitor of cell cycle progression. p27(Kip1) expression is induced in the primordial organ of Corti between E12 and E14, correlating with the cessation of cell division of the progenitors of the hair cells and supporting cells. In wild-type animals, p27(Kip1) expression is downregulated during subsequent hair cell differentiation, but it persists at high levels in differentiated supporting cells of the mature organ of Corti. In mice with a targeted deletion of the p27(Kip1) gene, proliferation of the sensory cell progenitors continues after E14, leading to the appearance of supernumerary hair cells and supporting cells. In the absence of p27(Kip1), mitotically active cells are still observed in the organ of Corti of postnatal day 6 animals, suggesting that the persistence of p27(Kip1) expression in mature supporting cells may contribute to the maintenance of quiescence in this tissue and, possibly, to its inability to regenerate. Homozygous mutant mice are severely hearing impaired. Thus, p27(Kip1) provides a link between developmental control of cell proliferation and the morphological development of the inner ear.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21228649 ◽

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.

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Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1003089107 ◽

2010 ◽

Vol 107 (36) ◽

pp. 15798-15803 ◽

Cited By ~ 83

Author(s):

W. Pan ◽

Y. Jin ◽

B. Stanger ◽

A. E. Kiernan

Keyword(s):

Notch Signaling ◽

Inner Ear ◽

Hair Cells ◽

Supporting Cells

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Hair Cells and Supporting Cells Share a Common Progenitor in the Avian Inner Ear

Journal of Neuroscience ◽

10.1523/jneurosci.18-19-07811.1998 ◽

1998 ◽

Vol 18 (19) ◽

pp. 7811-7821 ◽

Cited By ~ 148

Author(s):

Donna M. Fekete ◽

Shanthini Muthukumar ◽

Domna Karagogeos

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Supporting Cells ◽

Avian Inner Ear

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

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/264704 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 2

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.

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Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development

Development ◽

10.1242/dev.125.23.4645 ◽

1998 ◽

Vol 125 (23) ◽

pp. 4645-4654 ◽

Cited By ~ 17

Author(s):

J. Adam ◽

A. Myat ◽

I. Le Roux ◽

M. Eddison ◽

D. Henrique ◽

...

Keyword(s):

Inner Ear ◽

Cell Fate ◽

Hair Cells ◽

Early Stage ◽

Sense Organ ◽

Cell Types ◽

Developmental Pathways ◽

Supporting Cells ◽

Notch Ligand ◽

Developmental Program

The sensory patches in the vertebrate inner ear are similar in function to the mechanosensory bristles of a fly, and consist of a similar set of cell types. If they are truly homologous structures, they should also develop by similar mechanisms. We examine the genesis of the neurons, hair cells and supporting cells that form the sensory patches in the inner ear of the chick. These all arise from the otic epithelium, and are produced normally even in otic epithelium cultured in isolation, confirming that their production is governed by mechanisms intrinsic to the epithelium. First, the neuronal sublineage becomes separate from the epithelial: between E2 and E3.5, neuroblasts delaminate from the otocyst. The neuroblasts then give rise to a mixture of neurons and neuroblasts, while the sensory epithelial cells diversify to form a mixture of hair cells and supporting cells. The epithelial patches where this occurs are marked from an early stage by uniform and maintained expression of the Notch ligand Serrate1. The Notch ligand Delta1 is also expressed, but transiently and in scattered cells: it is seen both early, during neuroblast segregation, where it appears to be in the nascent neuroblasts, and again later, in the ganglion and in differentiating sensory patches, where it appears to be in the nascent hair cells, disappearing as they mature. Delta-Notch-mediated lateral inhibition may thus act at each developmental branchpoint to drive neighbouring cells along different developmental pathways. Our findings indicate that the sensory patches of the vertebrate inner ear and the sensory bristles of a fly are generated by minor variations of the same basic developmental program, in which cell diversification driven by Delta-Notch and/or Serrate-Notch signalling plays a central part.

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Research Progress on Flat Epithelium of the Inner Ear

Physiological Research ◽

10.33549/physiolres.934447 ◽

2020 ◽

pp. 775-785

Author(s):

L HE ◽

J-Y GUO ◽

K LIU ◽

G-P WANG ◽

S-S GONG

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Hair Cells ◽

Noise Exposure ◽

Sensory Epithelium ◽

Sensorineural Hearing ◽

Research Progress ◽

Supporting Cells ◽

Mesenchymal Transition

Sensorineural hearing loss and vertigo, resulting from lesions in the sensory epithelium of the inner ear, have a high incidence worldwide. The sensory epithelium of the inner ear may exhibit extreme degeneration and is transformed to flat epithelium (FE) in humans and mice with profound sensorineural hearing loss and/or vertigo. Various factors, including ototoxic drugs, noise exposure, aging, and genetic defects, can induce FE. Both hair cells and supporting cells are severely damaged in FE, and the normal cytoarchitecture of the sensory epithelium is replaced by a monolayer of very thin, flat cells of irregular contour. The pathophysiologic mechanism of FE is unclear but involves robust cell division. The cellular origin of flat cells in FE is heterogeneous; they may be transformed from supporting cells that have lost some features of supporting cells (dedifferentiation) or may have migrated from the flanking region. The epithelial-mesenchymal transition may play an important role in this process. The treatment of FE is challenging given the severe degeneration and loss of both hair cells and supporting cells. Cochlear implant or vestibular prosthesis implantation, gene therapy, and stem cell therapy show promise for the treatment of FE, although many challenges remain to be overcome.

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The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns

Neural Plasticity ◽

10.1155/2018/7513258 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Shaofeng Liu ◽

Yunfeng Wang ◽

Yongtian Lu ◽

Wen Li ◽

Wenjing Liu ◽

...

Keyword(s):

Transcription Factors ◽

Inner Ear ◽

Hair Cells ◽

Expression Patterns ◽

Organ Of Corti ◽

Sensory Organ ◽

Sensory Organs ◽

Supporting Cells ◽

Cell Fate Decisions ◽

Temporal And Spatial

Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures.

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Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling

Biomolecules ◽

10.3390/biom10030370 ◽

2020 ◽

Vol 10 (3) ◽

pp. 370 ◽

Cited By ~ 8

Author(s):

Rogers Brown ◽

Andrew K. Groves

Keyword(s):

Hair Cell ◽

Notch Signaling ◽

Inner Ear ◽

Hair Cells ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Supporting Cells ◽

Fine Grained

The vertebrate inner ear is responsible for detecting sound, gravity, and head motion. These mechanical forces are detected by mechanosensitive hair cells, arranged in a series of sensory patches in the vestibular and cochlear regions of the ear. Hair cells form synapses with neurons of the VIIIth cranial ganglion, which convey sound and balance information to the brain. They are surrounded by supporting cells, which nourish and protect the hair cells, and which can serve as a source of stem cells to regenerate hair cells after damage in non-mammalian vertebrates. The Notch signaling pathway plays many roles in the development of the inner ear, from the earliest formation of future inner ear ectoderm on the side of the embryonic head, to regulating the production of supporting cells, hair cells, and the neurons that innervate them. Notch signaling is re-deployed in non-mammalian vertebrates during hair cell regeneration, and attempts have been made to manipulate the Notch pathway to promote hair cell regeneration in mammals. In this review, we summarize the different modes of Notch signaling in inner ear development and regeneration, and describe how they interact with other signaling pathways to orchestrate the fine-grained cellular patterns of the ear.

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Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.660748 ◽

2021 ◽

Vol 15 ◽

Author(s):

Amrita A. Iyer ◽

Andrew K. Groves

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Hair Cell ◽

Inner Ear ◽

Cell Fate ◽

Hair Cells ◽

Cell Regeneration ◽

Cell Type ◽

Hair Cell Regeneration ◽

Supporting Cells

Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.

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