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

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.

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 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.

Notch signaling regulates the pattern of auditory hair cell differentiation in mammals

Development ◽  
2000 ◽  
Vol 127 (15) ◽  
pp. 3373-3383 ◽  
Author(s):  
A. Zine ◽  
T.R. Van De Water ◽  
F. de Ribaupierre
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Hair Cells ◽  
Expression Patterns ◽  
Sensory Epithelium ◽  
Supporting Cells ◽  
Hair Cell Differentiation ◽  
Notch1 Signaling Pathway

The development of the mammalian cochlea is an example of patterning in the peripheral nervous system. Sensory hair cells and supporting cells in the cochlea differentiate via regional and cell fate specification. The Notch signaling components shows both distinct and overlapping expression patterns of Notch1 receptor and its ligands Jagged1 (Jag1) and Jagged2 (Jag2) in the developing auditory epithelium of the rat. On embryonic day 16 (E16), many precursor cells within the Kolliker's organ immunostained for the presence of both Notch1 and Jag1, while the area of hair cell precursors did not express either Notch1 and Jag1. During initial events of hair cell differentiation between E18 and birth, Notch1 and Jag1 expression predominated in supporting cells and Jag2 in nascent hair cells. Early after birth, Jag2 expression decreased in hair cells while the pattern of Notch1 expression now included both supporting cells and hair cells. We show that the normal pattern of hair cell differentiation is disrupted by alteration of Notch signaling. A decrease of either Notch1 or Jag1 expression by antisense oligonucleotides in cultures of the developing sensory epithelium resulted in an increase in the number of hair cells. Our data suggest that the Notch1 signaling pathway is involved in a complex interplay between the consequences of different ligand-Notch1 combinations during cochlear morphogenesis and the phases of hair cell differentiation.

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 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 scRNA-Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Mark E Lush ◽  
Daniel C Diaz ◽  
Nina Koenecke ◽  
Sungmin Baek ◽  
Helena Boldt ◽  
...  
Keyword(s):  
Hair Cell ◽  
Notch Signaling ◽  
Lateral Line ◽  
Hair Cells ◽  
Cell Types ◽  
Developmental Trajectory ◽  
Cell Regeneration ◽  
Hair Cell Regeneration ◽  
Organ Regeneration ◽  
Hair Cell Differentiation

Loss of sensory hair cells leads to deafness and balance deficiencies. In contrast to mammalian hair cells, zebrafish ear and lateral line hair cells regenerate from poorly characterized support cells. Equally ill-defined is the gene regulatory network underlying the progression of support cells to differentiated hair cells. scRNA-Seq of lateral line organs uncovered five different support cell types, including quiescent and activated stem cells. Ordering of support cells along a developmental trajectory identified self-renewing cells and genes required for hair cell differentiation. scRNA-Seq analyses of fgf3 mutants, in which hair cell regeneration is increased, demonstrates that Fgf and Notch signaling inhibit proliferation of support cells in parallel by inhibiting Wnt signaling. Our scRNA-Seq analyses set the foundation for mechanistic studies of sensory organ regeneration and is crucial for identifying factors to trigger hair cell production in mammals. The data is searchable and publicly accessible via a web-based interface.

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.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
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

Neurons 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, leading to K+ accumulation. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.

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.

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