scholarly journals Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Hsin-I Jen ◽  
Matthew C Hill ◽  
Litao Tao ◽  
Kuanwei Sheng ◽  
Wenjian Cao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hair Cell ◽  
Cell Fate ◽  
Hair Cells ◽  
Cell Regeneration ◽  
Rna Seq ◽  
Hair Cell Regeneration ◽  
Supporting Cells ◽  
Ability To Regenerate ◽  
Accessible Chromatin

The mammalian cochlea loses its ability to regenerate new hair cells prior to the onset of hearing. In contrast, the adult vestibular system can produce new hair cells in response to damage, or by reprogramming of supporting cells with the hair cell transcription factor Atoh1. We used RNA-seq and ATAC-seq to probe the transcriptional and epigenetic responses of utricle supporting cells to damage and Atoh1 transduction. We show that the regenerative response of the utricle correlates with a more accessible chromatin structure in utricle supporting cells compared to their cochlear counterparts. We also provide evidence that Atoh1 transduction of supporting cells is able to promote increased transcriptional accessibility of some hair cell genes. Our study offers a possible explanation for regenerative differences between sensory organs of the inner ear, but shows that additional factors to Atoh1 may be required for optimal reprogramming of hair cell fate.

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

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.

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

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 370 ◽  
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.

scholarly journals Differential regulation of mammalian and avian ATOH1 by E2F1 and its implication for hair cell regeneration in the inner ear

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Miriam Gómez-Dorado ◽  
Nicolas Daudet ◽  
Jonathan E. Gale ◽  
Sally J. Dawson
Keyword(s):  
Transcription Factor ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Cell Cycle Progression ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Cell Regeneration ◽  
Hair Cell Regeneration ◽  
Age Related

AbstractThe mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1. Here, we show that members of the E2F transcription factor family, known to play a key role in cell cycle progression, regulate the expression of Atoh1. E2F1 activates chicken Atoh1 by directly interacting with a cis-regulatory region distal to the avian Atoh1 gene. E2F does not activate mouse Atoh1 gene expression, since this regulatory element is absent in mammals. We also show that E2F1 expression changes dynamically in the chicken auditory epithelium during ototoxic damage and hair cell regeneration. Therefore, we propose a model in which the mitotic regeneration of non-mammalian hair cells is due to E2F1-mediated activation of Atoh1 expression, a mechanism which has been lost in mammals.

Hair cell regeneration after acoustic trauma in adult Coturnix quail

Science ◽  
1988 ◽  
Vol 240 (4860) ◽  
pp. 1774-1776 ◽  
Author(s):  
BM Ryals ◽  
EW Rubel
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Cell Loss ◽  
Acoustic Trauma ◽  
Cell Regeneration ◽  
Hair Cell Loss ◽  
Hair Cell Regeneration ◽  
Supporting Cells ◽  
Coturnix Quail ◽  
Original Number

Recovery of hair cells was studied at various times after acoustic trauma in adult quail. An initial loss of hair cells recovered to within 5 percent of the original number of cells. Tritium-labeled thymidine was injected after this acoustic trauma to determine if mitosis played a role in recovery of hair cells. Within 10 days of acoustic trauma, incorporation of [3H]thymidine was seen over the nuclei of hair cells and supporting cells in the region of initial hair cell loss. Thus, hair cell regeneration can occur after embryonic terminal mitosis.

Delta1 expression during avian hair cell regeneration

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 961-973 ◽  
Author(s):  
J.S. Stone ◽  
E.W. Rubel
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Cell Injury ◽  
Basilar Papilla ◽  
Cell Regeneration ◽  
Mrna Levels ◽  
Hair Cell Regeneration ◽  
Drug Induced ◽  
In Cells

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.

scholarly journals The challenge of hair cell regeneration

2010 ◽  
Vol 235 (4) ◽  
pp. 434-446 ◽  
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.

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

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.

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

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.

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

2020 ◽  
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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