Selective Ablation of Inner Hair Cells and Subsequent In-situ Hair Cell Regeneration in the Neonatal Mouse Cochlea

Postembryonic production of hair cells, the highly specialized receptors for hearing, balance and motion detection, occurs in a precisely controlled manner in select species, including avians. Notch1, Delta1 and Serrate1 mediate cell specification in several tissues and species. We examined expression of the chicken homologs of these genes in the normal and drug-damaged chick inner ear to determine if signaling through this pathway changes during hair cell regeneration. In untreated post-hatch chicks, Delta1 mRNA is abundant in a subpopulation of cells in the utricle, which undergoes continual postembryonic hair cell production, but it is absent from all cells in the basilar papilla, which is mitotically quiescent. By 3 days after drug-induced hair cell injury, Delta1 expression is highly upregulated in areas of cell proliferation in both the utricle and basilar papilla. Delta1 mRNA levels are elevated in progenitor cells during DNA synthesis and/or gap 2 phases of the cell cycle and expression is maintained in both daughter cells immediately after mitosis. Delta1 expression remains upregulated in cells that differentiate into hair cells and is downregulated in cells that do not acquire the hair cell fate. Delta1 mRNA levels return to normal by 10 days after hair cell injury. Serrate1 is expressed in both hair cells and support cells in the utricle and basilar papilla, and its expression does not change during the course of drug-induced hair cell regeneration. In contrast, Notch1 expression, which is limited to support cells in the quiescent epithelium, is increased in post-M-phase cell pairs during hair cell regeneration. This study provides initial evidence that Delta-Notch signaling may be involved in maintaining the correct cell types and patterns during postembryonic replacement of sensory epithelial cells in the chick inner ear.

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Multiple supporting cell subtypes are capable of spontaneous hair cell regeneration in the neonatal mouse cochlea

Development ◽

10.1242/dev.171009 ◽

2019 ◽

Vol 146 (4) ◽

pp. dev171009 ◽

Cited By ~ 7

Author(s):

Melissa M. McGovern ◽

Michelle R. Randle ◽

Candice L. Cuppini ◽

Kaley A. Graves ◽

Brandon C. Cox

Keyword(s):

Hair Cell ◽

Supporting Cell ◽

Neonatal Mouse ◽

Cell Regeneration ◽

Hair Cell Regeneration

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The challenge of hair cell regeneration

Experimental Biology and Medicine ◽

10.1258/ebm.2009.009281 ◽

2010 ◽

Vol 235 (4) ◽

pp. 434-446 ◽

Cited By ~ 77

Author(s):

Andrew K Groves

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Electrical Energy ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Therapeutic Approaches ◽

Auditory Hair Cells ◽

Sensory Hair Cells ◽

Ototoxic Drugs ◽

Effects Of Aging

Sensory hair cells of the inner ear are responsible for translating auditory or vestibular stimuli into electrical energy that can be perceived by the nervous system. Although hair cells are exquisitely mechanically sensitive, they can be easily damaged by excessive stimulation by ototoxic drugs and by the effects of aging. In mammals, auditory hair cells are never replaced, such that cumulative damage to the ear causes progressive and permanent deafness. In contrast, non-mammalian vertebrates are capable of replacing lost hair cells, which has led to efforts to understand the molecular and cellular basis of regenerative responses in different vertebrate species. In this review, we describe recent progress in understanding the limits to hair cell regeneration in mammals and discuss the obstacles that currently exist for therapeutic approaches to hair cell replacement.

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Macrophages Respond Rapidly to Ototoxic Injury of Lateral Line Hair Cells but Are Not Required for Hair Cell Regeneration

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.613246 ◽

2021 ◽

Vol 14 ◽

Author(s):

Mark E. Warchol ◽

Angela Schrader ◽

Lavinia Sheets

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Lateral Line ◽

Hair Cells ◽

Control Fish ◽

Cell Regeneration ◽

Cellular Interactions ◽

Hair Cell Regeneration ◽

Genetic Ablation ◽

Larval Zebrafish

The sensory organs of the inner ear contain resident populations of macrophages, which are recruited to sites of cellular injury. Such macrophages are known to phagocytose the debris of dying cells but the full role of macrophages in otic pathology is not understood. Lateral line neuromasts of zebrafish contain hair cells that are nearly identical to those in the inner ear, and the optical clarity of larval zebrafish permits direct imaging of cellular interactions. In this study, we used larval zebrafish to characterize the response of macrophages to ototoxic injury of lateral line hair cells. Macrophages migrated into neuromasts within 20 min of exposure to the ototoxic antibiotic neomycin. The number of macrophages in the near vicinity of injured neuromasts was similar to that observed near uninjured neuromasts, suggesting that this early inflammatory response was mediated by “local” macrophages. Upon entering injured neuromasts, macrophages actively phagocytosed hair cell debris. The injury-evoked migration of macrophages was significantly reduced by inhibition of Src-family kinases. Using chemical-genetic ablation of macrophages before the ototoxic injury, we also examined whether macrophages were essential for the initiation of hair cell regeneration. Results revealed only minor differences in hair cell recovery in macrophage-depleted vs. control fish, suggesting that macrophages are not essential for the regeneration of lateral line hair cells.

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Development and evolution of the vestibular sensory apparatus of the mammalian ear

Journal of Vestibular Research ◽

10.3233/ves-2005-155-601 ◽

2005 ◽

Vol 15 (5-6) ◽

pp. 225-241

Author(s):

Kirk W. Beisel ◽

Yesha Wang-Lundberg ◽

Adel Maklad ◽

Bernd Fritzsch

Keyword(s):

Hair Cell ◽

Protein Interactions ◽

Hair Cells ◽

Single Gene ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Horizontal Canal ◽

Evolutionary Changes ◽

Hair Cell Differentiation ◽

Molecular Aspects

Herein, we will review molecular aspects of vestibular ear development and present them in the context of evolutionary changes and hair cell regeneration. Several genes guide the development of anterior and posterior canals. Although some of these genes are also important for horizontal canal development, this canal strongly depends on a single gene, Otx1. Otx1 also governs the segregation of saccule and utricle. Several genes are essential for otoconia and cupula formation, but protein interactions necessary to form and maintain otoconia or a cupula are not yet understood. Nerve fiber guidance to specific vestibular end-organs is predominantly mediated by diffusible neurotrophic factors that work even in the absence of differentiated hair cells. Neurotrophins, in particular Bdnf, are the most crucial attractive factor released by hair cells. If Bdnf is misexpressed, fibers can be redirected away from hair cells. Hair cell differentiation is mediated by Atoh1. However, Atoh1 may not initiate hair cell precursor formation. Resolving the role of Atoh1 in postmitotic hair cell precursors is crucial for future attempts in hair cell regeneration. Additional analyses are needed before gene therapy can help regenerate hair cells, restore otoconia, and reconnect sensory epithelia to the brain.

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Suppression of Inflammation Delays Hair Cell Regeneration and Functional Recovery Following Lateral Line Damage in Zebrafish Larvae

10.1101/2020.02.26.962753 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ru Zhang ◽

Xiao-Peng Liu ◽

Ya-Juan Li ◽

Ming Wang ◽

Lin Chen ◽

...

Keyword(s):

Hair Cell ◽

Functional Recovery ◽

Lateral Line ◽

Hair Cells ◽

Calcium Imaging ◽

Inflammatory Responses ◽

Early Stage ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Cochlear Hair Cells

AbstractBackgroundHuman cochlear hair cells cannot spontaneously regenerate after loss. In contrast, those in fish and amphibians have a remarkable ability to regenerate after damaged. Previous studies focus on signaling mechanisms of hair cell regeneration, such as Wnt and Notch signals but seldom on the fact that the beginning of regeneration is accompanied by a large number of inflammatory responses. The detailed role of this inflammation in hair cell regeneration is still unknown. In addition, there is no appropriate behavioral method to quantitatively evaluate the functional recovery of lateral line hair cells after regeneration.ResultsIn this study, we found that when inflammation was suppressed, the regeneration of lateral line hair cells and the recovery of the rheotaxis of the larvae were significantly delayed. Calcium imaging showed that the function of the neuromasts in the inflammation-inhibited group was weaker than that in the non-inflammation-inhibited group at the Early Stage of regeneration, and returned to normal at the Late Stage. Calcium imaging also revealed the cause of the mismatch between the function and quantity during regeneration.ConclusionsOur results, meanwhile, suggest that suppressing inflammation delays hair cell regeneration and functional recovery when hair cells are damaged. This study may provide a new knowledge for how to promote hair cell regeneration and functional recovery in adult mammals.

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Comparing Sensory Organs to Define the Path for Hair Cell Regeneration

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-100818-125503 ◽

2019 ◽

Vol 35 (1) ◽

pp. 567-589 ◽

Cited By ~ 5

Author(s):

Nicolas Denans ◽

Sungmin Baek ◽

Tatjana Piotrowski

Keyword(s):

Hair Cell ◽

Olfactory Epithelium ◽

Current Literature ◽

Hair Cells ◽

Sensory Cell ◽

Cell Regeneration ◽

Hair Cell Regeneration ◽

Sensory Hair ◽

Sensory Hair Cells ◽

Technical Advances

Deafness or hearing deficits are debilitating conditions. They are often caused by loss of sensory hair cells or defects in their function. In contrast to mammals, nonmammalian vertebrates robustly regenerate hair cells after injury. Studying the molecular and cellular basis of nonmammalian vertebrate hair cell regeneration provides valuable insights into developing cures for human deafness. In this review, we discuss the current literature on hair cell regeneration in the context of other models for sensory cell regeneration, such as the retina and the olfactory epithelium. This comparison reveals commonalities with, as well as differences between, the different regenerating systems, which begin to define a cellular and molecular blueprint of regeneration. In addition, we propose how new technical advances can address outstanding questions in the field.

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Recovery of the Vestibulocolic Reflex After Aminoglycoside Ototoxicity in Domestic Chickens

Journal of Neurophysiology ◽

10.1152/jn.1999.81.3.1025 ◽

1999 ◽

Vol 81 (3) ◽

pp. 1025-1035 ◽

Cited By ~ 15

Author(s):

Christopher T. Goode ◽

John P. Carey ◽

Albert F. Fuchs ◽

Edwin W Rubel

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Afferent Input ◽

Open Loop ◽

Cell Regeneration ◽

Type I ◽

Neural Pathways ◽

Hair Cell Regeneration ◽

Vestibular Hair Cells ◽

Aminoglycoside Ototoxicity

Recovery of the vestibulocolic reflex after aminoglycoside ototoxicity in domestic chickens. Avian auditory and vestibular hair cells regenerate after damage by ototoxic drugs, but until recently there was little evidence that regenerated vestibular hair cells function normally. In an earlier study we showed that the vestibuloocular reflex (VOR) is eliminated with aminoglycoside antibiotic treatment and recovers as hair cells regenerate. The VOR, which stabilizes the eye in the head, is an open-loop system that is thought to depend largely on regularly firing afferents. Recovery of the VOR is highly correlated with the regeneration of type I hair cells. In contrast, the vestibulocolic reflex (VCR), which stabilizes the head in space, is a closed-loop, negative-feedback system that seems to depend more on irregularly firing afferent input and is thought to be subserved by different circuitry than the VOR. We examined whether this different reflex also of vestibular origin would show similar recovery after hair cell regeneration. Lesions of the vestibular hair cells of 10-day-old chicks were created by a 5-day course of streptomycin sulfate. One day after completion of streptomycin treatment there was no measurable VCR gain, and total hair cell density was ∼35% of that in untreated, age-matched controls. At 2 wk postlesion there was significant recovery of the VCR; at this time two subjects showed VCR gains within the range of control chicks. At 3 wk postlesion all subjects showed VCR gains and phase shifts within the normal range. These data show that the VCR recovers before the VOR. Unlike VOR gain, recovering VCR gain correlates equally well with the density of regenerating type I and type II vestibular hair cells, except at high frequencies. Several factors other than hair cell regeneration, such as length of stereocilia, reafferentation of hair cells, and compensation involving central neural pathways, may be involved in behavioral recovery. Our data suggest that one or more of these factors differentially affect the recovery of these two vestibular reflexes.

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