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

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.

Download Full-text

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

Nature ◽

10.1038/nature04849 ◽

2006 ◽

Vol 441 (7096) ◽

pp. 984-987 ◽

Cited By ~ 262

Author(s):

Patricia M. White ◽

Angelika Doetzlhofer ◽

Yun Shain Lee ◽

Andrew K. Groves ◽

Neil Segil

Keyword(s):

Hair Cells ◽

Supporting Cells ◽

Cochlear Supporting Cells

Download Full-text

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

PLoS ONE ◽

10.1371/journal.pone.0260443 ◽

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.

Download Full-text

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

10.1101/2021.01.21.427665 ◽

2021 ◽

Author(s):

Suhong Sun ◽

Shuting Li ◽

Zhengnan Luo ◽

Minhui Ren ◽

Shunji He ◽

...

Keyword(s):

Single Cell ◽

Hearing Impairment ◽

Hair Cells ◽

Outer Hair Cells ◽

Supporting Cells ◽

Differentiation Status ◽

Cochlear Supporting Cells ◽

Simultaneous Expression ◽

Dual Expression

ABSTRACTMammalian cochlear outer hair cells (OHCs) are essential for hearing. OHC degeneration causes severe hearing impairment. Previous attempts of regenerating new OHCs from cochlear supporting cells (SCs) had yielded cells lacking Prestin, a key motor protein for OHC function. Thus, regeneration of Prestin+ OHCs remains a challenge for repairing OHC damage in vivo. Here, we reported that successful in vivo conversion of adult cochlear SCs into Prestin+ OHC-like cells could be achieved by simultaneous expression of Atoh1 and Ikzf2, two key transcriptional factors necessary for OHC development. New OHC-like cells exhibited upregulation of hundreds of OHC genes and downregulation of SC genes. Single cell transcriptomic analysis demonstrated that the differentiation status of these OHC-like cells was much more advanced than previously achieved. Thus, we have established an efficient approach to promote regeneration of Prestin+ OHCs and paved the way for repairing damaged cochlea in vivo via transdifferentiation of SCs.

Download Full-text

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

eLife ◽

10.7554/elife.66547 ◽

2021 ◽

Vol 10 ◽

Author(s):

Suhong Sun ◽

Shuting Li ◽

Zhengnan Luo ◽

Minhui Ren ◽

Shunji He ◽

...

Keyword(s):

Hair Cells ◽

Adult Mouse ◽

Outer Hair Cells ◽

Auditory Function ◽

Supporting Cells ◽

Single Cell Rna Sequencing ◽

Differentiation Status ◽

Cochlear Supporting Cells ◽

Dual Expression

Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single-cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

Download Full-text

Efferent neurons control hearing sensitivity and protect hearing from noise through the regulation of gap junctions between cochlear supporting cells

Journal of Neurophysiology ◽

10.1152/jn.00468.2021 ◽

2021 ◽

Author(s):

Hong-Bo Zhao ◽

Li-Man Liu ◽

Ning Yu ◽

Yan Zhu ◽

Ling Mei ◽

...

Keyword(s):

Gap Junctions ◽

Hair Cells ◽

Nerve Fibers ◽

Supporting Cells ◽

Hearing Sensitivity ◽

Efferent System ◽

Efferent Pathway ◽

Cochlear Amplification ◽

Efferent Neurons ◽

Cochlear Supporting Cells

It is critical for hearing that the descending cochlear efferent system provide a negative feedback to hair cells to regulate hearing sensitivity and provide the protection of hearing from noise. Here, we report that the medial olivocochlear (MOC) efferent nerves, which project to outer hair cells (OHCs), also could innervate OHC surrounding supporting cells (SCs) to regulate hearing sensitivity. MOC nerve fibers are cholinergic and acetylcholine (ACh) is a primary neurotransmitter. MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChT), and postsynaptic ACh receptors were visible in SCs and the SC area. Application of ACh in the SC could evoke a typical inward current, which reduced gap junctions (GJs) between SCs and consequently declined OHC electromotility, which is an active cochlear amplification and can increase hearing sensitivity. This indirect, GJ-mediated inhibition enhanced the direct inhibition of ACh on OHC electromotility but had long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway declined the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion production otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this GJ-mediated efferent pathway may play a critical role in the long-term efferent inhibition and is required for protecting hearing from noise trauma.

Download Full-text

In vivo optogenetics reveals homeostatic control of cochlear sensitivity by supporting cells

10.21203/rs.3.rs-92461/v1 ◽

2020 ◽

Author(s):

Victoria Lukashkina ◽

Snezana Levic ◽

Patricio Simões ◽

Zhenhang Xu ◽

Joseph DiGuiseppi ◽

...

Keyword(s):

Hair Cells ◽

Dynamic Range ◽

Organ Of Corti ◽

Feedback System ◽

Supporting Cell ◽

Outer Hair Cells ◽

Supporting Cells ◽

Cochlear Supporting Cells

Abstract We used optogenetics to investigate the control of auditory sensitivity by cochlear supporting cells that scaffold outer hair cells, which transduce and amplify cochlear responses to sound. In vivo and in vitro measurements of sound-induced cochlear mechanical and electrical responses were made from mice that conditionally expressed nonselective cationic channelrhodopsins in Deiters’ and outer pillar supporting cells in the organ of Corti. We demonstrated that cochlear light-stimulation and subsequent activation of channelrhodopsins depolarized the supporting cells, changed their extracellular electrical environment, and sensitized insensitive and desensitized sensitive cochlear responses to sound. We concluded that outer hair cells, Deiters’ cells and outer pillar cells interact through feedback which regulates their immediate ionic and electrical environment and controls energy flow in the mammalian cochlea to optimize its performance over its entire dynamic range. Activation of the supporting cell channelrhodopsins shunts this feedback system and restores cochlear sensitivity to a set level.

Download Full-text

Cochlear organoids reveal epigenetic and transcriptional programs of postnatal hair cell differentiation from supporting cells

10.1101/2021.09.19.460948 ◽

2021 ◽

Author(s):

Gurmannat Kalra ◽

Danielle Lenz ◽

Dunia Abdul-Aziz ◽

Craig Hanna ◽

Brian Herb ◽

...

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Regulatory Networks ◽

Hair Cell Regeneration ◽

Cell Fates ◽

Supporting Cells ◽

Enhancer Binding Protein ◽

Full Picture ◽

Hair Cell Differentiation ◽

Cochlear Supporting Cells

We explored the transcriptional and epigenetic programs underlying the differentiation of hair cells from postnatal progenitor cells in cochlear organoids. Heterogeneity in the cells including cells with the transcriptional signatures of mature hair cells allowed a full picture of possible cell fates. Construction of trajectories identified Lgr5+ cells as progenitors for hair cells and the genomic data revealed gene regulatory networks leading to hair cells. We validated these networks, demonstrating dynamic changes both in expression and predicted binding sites of these transcription factors during organoid differentiation. We identified known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and predicted novel regulatory factors, Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for HC regeneration which is limited in the adult.

Download Full-text

Faculty Opinions recommendation of Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033188.375166 ◽

2006 ◽

Author(s):

Martine Roussel

Keyword(s):

Hair Cells ◽

Supporting Cells ◽

Cochlear Supporting Cells

Download Full-text

Efferent control of hearing sensitivity and protection via inner ear supporting cells

10.1101/2020.12.03.409946 ◽

2020 ◽

Author(s):

Hong-Bo Zhao ◽

Li-Man Liu ◽

Ling Mei ◽

Ning Yu ◽

Jin Chen ◽

...

Keyword(s):

Hair Cells ◽

Nerve Fibers ◽

Dependent Manner ◽

Supporting Cells ◽

Noise Trauma ◽

Hearing Sensitivity ◽

Efferent System ◽

Efferent Control ◽

Cochlear Amplification ◽

Cochlear Supporting Cells

It is critical for hearing that the descending cochlear efferent system provide negative feedback to hair cells to regulate hearing sensitivity and provide protection from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) and inhibit OHC electromotility, which is an active cochlear amplification and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also have functional innervation with the cochlear supporting cells to regulate hearing sensitivity. The MOC efferent nerve fibers and the corresponding MOC neurotransmitter acetylcholine (ACh) receptors were visible in the cochlear supporting cells. Application of ACh in the cochlear supporting cells could also evoke inward currents in a dose-dependent manner and reduced gap junctional (GJ) coupling between the cochlear supporting cells, which consequently declined electromotility in OHCs. This indirect inhibitory effect through the mediated GJs between the cochlear supporting cells on OHC electromotility was consistent and enhanced the direct inhibition of ACh on OHC electromotility but had long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent control pathway declined the regulation of active cochlear amplification and impaired the protection from noise trauma. Our findings reveal a new pathway for the cochlear efferent system to control hearing sensitivity, and also demonstrate that this supporting cell GJ-mediated efferent pathway is critical for control of hearing sensitivity and the protection of hearing from noise trauma.

Download Full-text