Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea

Abstract Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low...

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Autores principales:	Sungsu Lee, Jae-Jun Song, Lisa A. Beyer, Donald L. Swiderski, Diane M. Prieskorn, Melih Acar, Hsin-I Jen, Andrew K. Groves, Yehoash Raphael
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a5f302ca620148b1ae8d55867529301b
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spelling	oai:doaj.org-article:a5f302ca620148b1ae8d55867529301b2021-12-02T16:18:06ZCombinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea10.1038/s41598-020-78167-82045-2322https://doaj.org/article/a5f302ca620148b1ae8d55867529301b2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78167-8https://doaj.org/toc/2045-2322Abstract Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1 + Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1 + Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1 + Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.Sungsu LeeJae-Jun SongLisa A. BeyerDonald L. SwiderskiDiane M. PrieskornMelih AcarHsin-I JenAndrew K. GrovesYehoash RaphaelNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sungsu Lee Jae-Jun Song Lisa A. Beyer Donald L. Swiderski Diane M. Prieskorn Melih Acar Hsin-I Jen Andrew K. Groves Yehoash Raphael Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
description	Abstract Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1 + Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1 + Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1 + Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.
format	article
author	Sungsu Lee Jae-Jun Song Lisa A. Beyer Donald L. Swiderski Diane M. Prieskorn Melih Acar Hsin-I Jen Andrew K. Groves Yehoash Raphael
author_facet	Sungsu Lee Jae-Jun Song Lisa A. Beyer Donald L. Swiderski Diane M. Prieskorn Melih Acar Hsin-I Jen Andrew K. Groves Yehoash Raphael
author_sort	Sungsu Lee
title	Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
title_short	Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
title_full	Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
title_fullStr	Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
title_full_unstemmed	Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea
title_sort	combinatorial atoh1 and gfi1 induction enhances hair cell regeneration in the adult cochlea
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/a5f302ca620148b1ae8d55867529301b
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Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea

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