scholarly journals TUB and ZNF532 Promote the Atoh1-Mediated Hair Cell Regeneration in Mouse Cochleae

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhenhang Xu ◽  
Vikrant Rai ◽  
Jian Zuo
Keyword(s):  
Transcription Factors ◽  
Hair Cell ◽  
Ex Vivo ◽  
Ectopic Expression ◽  
Explant Culture ◽  
Cell Regeneration ◽  
Hair Cell Regeneration ◽  
Supporting Cells ◽  
Minimal Damage

Hair cell (HC) regeneration is a promising therapy for permanent sensorineural hearing loss caused by HC loss in mammals. Atoh1 has been shown to convert supporting cells (SCs) to HCs in neonatal cochleae; its combinations with other factors can improve the efficiency of HC regeneration. To identify additional transcription factors for efficient Atoh1-mediated HC regeneration, here we optimized the electroporation procedure for explant culture of neonatal mouse organs of Corti and tested multiple transcription factors, Six2, Ikzf2, Lbh, Arid3b, Hmg20 a, Tub, Sall1, and Znf532, for their potential to promote Atoh1-mediated conversion of SCs to HCs. These transcription factors are expressed highly in HCs but differentially compared to the converted HCs based on previous studies, and are also potential co-reprograming factors for Atoh1-mediated SC-to-HC conversion by literature review. P0.5 cochlear explants were electroporated with these transcription factors alone or jointly with Atoh1. We found that Sox2+ progenitors concentrated within the lateral greater epithelial ridge (GER) can be electroporated efficiently with minimal HC damage. Atoh1 ectopic expression promoted HC regeneration in Sox2+ lateral GER cells. Transcription factors Tub and Znf532, but not the other six tested, promoted the HC regeneration mediated by Atoh1, consistent with previous studies that Isl1 promotes Atoh1-mediated HC conversionex vivo and in vivo and that both Tub and Znf532 are downstream targets of Isl1. Thus, our studies revealed an optimized electroporation method that can transfect the Sox2+ lateral GER cells efficiently with minimal damage to the endogenous HCs. Our results also demonstrate the importance of the Isl1/Tub/Znf532 pathway in promoting Atoh1-mediated HC regeneration.

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 Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27 kip and sox2 in Supporting Cells

2015 ◽  
Vol 35 (47) ◽  
pp. 15752-15766 ◽  
Author(s):  
Davide Rubbini ◽  
Àlex Robert-Moreno ◽  
Esteban Hoijman ◽  
Berta Alsina
Keyword(s):  
Retinoic Acid ◽  
Hair Cell ◽  
Cell Regeneration ◽  
Retinoic Acid Signaling ◽  
Hair Cell Regeneration ◽  
Supporting Cells

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 Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo

Development ◽  
2014 ◽  
Vol 141 (7) ◽  
pp. 1599-1599 ◽  
Author(s):  
B. C. Cox ◽  
R. Chai ◽  
A. Lenoir ◽  
Z. Liu ◽  
L. Zhang ◽  
...  
Keyword(s):  
Hair Cell ◽  
Neonatal Mouse ◽  
Cell Regeneration ◽  
Hair Cell Regeneration

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 Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo

Development ◽  
2014 ◽  
Vol 141 (4) ◽  
pp. 816-829 ◽  
Author(s):  
B. C. Cox ◽  
R. Chai ◽  
A. Lenoir ◽  
Z. Liu ◽  
L. Zhang ◽  
...  
Keyword(s):  
Hair Cell ◽  
Neonatal Mouse ◽  
Cell Regeneration ◽  
Hair Cell Regeneration
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