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Sensory cells give hope to restoring hearing

In a first, investigators at St. Jude Children's Research Hospital can genetically manipulate auditory hair cells to regenerate in mice. This marks an advance which may lead to treatment of hearing loss in humans.


Loss of auditory hair cells can happen from prolonged exposure to loud noise, accidents, illness, aging or even medications. The loss of these hair cells is a leading cause of hearing loss in adults worldwide. Some childhood cancer survivors are also at risk as hair cells can be damaged by some chemotherapy medications. Treatment so far has been focused on electronic devices like hearing aids and cochlear implants. Once lost, human auditory hair cells do not regrow.

According to Jian Zuo PhD, Department of Developmental Neurobiology, St. Jude Hospital in Memphis, Tennessee: "We looked to Mother Nature for answers and were rewarded. Unlike humans, auditory hair cells do regenerate in fish and chicken. The process involves down-regulating expression of the protein p27 and up-regulating expression of the protein Atoh1. So, we tried the same approach in specially bred mice."


By manipulating proteins p27 and Atoh1, Zuo and his colleagues induced the supporting hair cells within the inner ears of mice to act as immature hair cells. These immature hair cells then began producing the signature proteins of inner ear hair cells — and grew.


ATOH1 is a transcription factor needed for hair cell development. In humans and other mammals, the gene is switched off when hair cell growth is completed — which in humans is before birth. Their study appears in the journal Cell Reports.


Researchers identified in mice a genetic pathway for inner ear hair cell regeneration, detailing which proteins foster hair cell regrowth. They are GATA3 and POU4F3, along with p27 and ATOH1. They also established how POU4F3 alone could regenerate hair cells — but volume increased by adding ATOH1.


P27 protein is best known for stopping cell proliferation. In this study, p27 was seen to stop GATA3 production. As GATA3 and ATOH1 work together to increase expression of POU4F3, reducing GATA3 reduced POU4F3 as well. When the p27 gene was deleted, GATA3 increased along with function of POU4F3, and hair cell regeneration increased as well.


"This study suggests targeting [proteins] p27, GATA3 and POU4F3 may enhance the outcome of gene therapy and ... restart ATOH1 expression."

Jian Zuo PhD, Department of Developmental Neurobiology, St. Jude Hospital, Memphis, Tennessee, USA.


Study findings helped to initiate a phase 1 clinical trial, now underway, which is using gene therapy to restart ATOH1 function in an attempt to regenerate human hair cells.

Zuo adds: "Work in other organs has shown that reprogramming cells is rarely accomplished by manipulating a single factor. This study suggests that supporting cells in the cochlea are no exception. Work continues to identify other factors, including small molecules, necessary to not only promote the maturation and survival of the newly generated hair cells, but also increase their number,"

Highlights
• Co-manipulation of ATOH1 and p27Kip1 creates new cochlear hair cells in adult mice
• p27Kip1 noncanonically inhibits GATA3, an Atoh1 co-factor that promotes POU4F3
• Ectopic POU4F3 upregulates hair cell markers in supporting cells in adult cochleae
• ATOH1-based therapies may be improved by comanipulation of p27Kip1, GATA3, or POU4F3Abstract

Summary
Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.

The first author is Bradley Walters, Ph.D., formerly of St. Jude. The other authors are Jennifer Dearman, Tetsuji Yamashita and Bryan Kuo, all of St. Jude, and Emily Coak and Grace Bailey, both visiting students from Bath University, United Kingdom, and formerly of St. Jude.

The study was supported in part by grants (DC006471, DC015010, DC015444, DC013879, CA21765) from the National Institutes of Health; grants (N000140911014, N000141210191, N000141210775, N000141612315) from the Office of Naval Research; the National Organization for Hearing Research Foundation; the Hearing Health Foundation; the Hartwell Foundation; and ALSAC, the fundraising arm of St. Jude.
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Apr 19, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



In humans, auditory hair cells cannot regenerate - at least, that is the canon or "law."
Human inner ear or auditory hair cells that become damaged can cause total loss of hearing.
In adult mice, the Atoh1gene helps convert non-sensory cells into becomming auditory hair cells.
The same Atoh1gene in humans is switched off before birth - maybe it can be turned back on.
Image Credit:
Cell Reports

 


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