Cell Regeneration

Success of Sensory Cell Regeneration Raises Hope for Hearing Restoration

By St. Jude Children's Research Hospital

Jian Zuo, Ph.D., and his colleagues induced supporting cells located in the inner ear of adult mice to take on the appearance of immature hair cells and to begin producing some of the signature proteins of hair cells.

Jian Zuo, Ph.D., and his colleagues induced supporting cells located in the inner ear of adult
mice to take on the appearance of immature hair cells and to begin producing some of the signature proteins of hair cells.

In an apparent first, St. Jude Children's Research Hospital investigators have used genetic manipulation to regenerate auditory hair cells in adult mice. The research marks a possible advance in treatment of hearing loss in humans. The study appears today in the journal Cell Reports.

Loss of auditory hair cells due to prolonged exposure to loud noise, accidents, illness, aging or medication is a leading cause of hearing loss and long-term disability in adults worldwide. Some childhood cancer survivors are also at risk because of hair cells damage due to certain chemotherapy agents. Treatment has focused on electronic devices like hearing aids or cochlear implants because once lost, human auditory hair cells do not grow back.

"In this study, we looked to Mother Nature for answers and we were rewarded," said corresponding author Jian Zuo, Ph.D., a member of the St. Jude Department of Developmental Neurobiology. "Unlike in humans, auditory hair cells do regenerate in fish and chicken. The process involves down-regulating expression of the protein p27 and up-regulating the expression of the protein Atoh1. So we tried the same approach in specially bred mice."

By manipulating the same genes, Zuo and his colleagues induced supporting cells located in the inner ear of adult mice to take on the appearance of immature hair cells and to begin producing some of the signature proteins of hair cells.

The scientists also identified a genetic pathway for hair cell regeneration and detailed how proteins in that pathway cooperate to foster the process. The pathway includes the proteins GATA3 and POU4F3 along with p27 and ATOH1. In fact, investigators found that POU4F3 alone was sufficient to regenerate hair cells, but that more hair cells were regenerated when both ATOH1 and POU4F3 were involved.

"Work in other organs has shown that reprogramming cells is rarely accomplished by manipulating a single factor," Zuo said. "This study suggests that supporting cells in the cochlea are no exception and may benefit from therapies that target the proteins identified in this study."

The findings have implications for a phase 1 clinical trial now underway that uses gene therapy to restart expression of ATOH1 to regenerate hair cells for treatment of hearing loss.

ATOH1 is a transcription factor necessary for hair cell development. In humans and other mammals, the gene is switched off when the process is complete. In humans, ATOH1 production ceases before birth.

"This study suggests that targeting p27, GATA3 and POU4F3 may enhance the outcome of gene therapy and other approaches that aim to restart ATOH1 expression," Zuo said.

The research also revealed a novel role for p27. The protein is best known as serving as a check on cell proliferation. However, in this study p27 suppressed GATA3 production. Since GATA3 and ATOH1 work together to increase expression of POU4F3, reducing GATA3 levels also reduced expression of POU4F3. When the p27 gene was deleted in mice, GATA3 levels increased along with expression of POU4F3. Hair cell regeneration increased as well.

"Work continues to identify the 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," Zuo said.

Bradley J. Walters, Ph.D. was a 2012 Hearing Health Foundation Emerging Research Grants recipient. This article was repurpsed with permission. 

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The HRP Shifts Gears for Greater Impact

By Peter Barr-Gillespie, Ph.D.

It’s remarkable to me that the Hearing Restoration Project (HRP) is five years old! While the past five years revealed that regeneration of sensory hair cells is more complex than anticipated, our scientists have nonetheless made significant progress. Several notable HRP research projects supported by Hearing Health Foundation (HHF) were published in 2016, and more are on the way.

Financial investment in the HRP is crucial for our success. Through the HRP, HHF supports promising innovative research areas that due to the lack of available funds are not adequately financed by other agencies. We continue to acquire large-scale genomics datasets, and the more we generate the more valuable they all are—comparing the results from different types of experiments is a key approach of the HRP.

In 2017 we will see a change in the way the HRP conducts its research. At our HRP meeting this past November, the consortium updated its research methods for the upcoming year, choosing to focus and devote more resources on two promising, major experimental strategies. This is a shift from the approach over the past five years, when the HRP followed various independent paths to understanding hair cell regeneration.

The first project will use “single-cell sequencing” experiments, which will reveal the molecular processes of hair cell regeneration in chicks and fish with unprecedented resolution. Single-cell methods allow us to examine thousands of genes in hundreds of individually isolated supporting cells, some of which are responding to hair cell damage.

With these voluminous datasets, we will then describe the succession of molecular changes needed to regenerate hair cells. Results from these experiments will be compared with similar experiments examining hair cell damage in mice, which like all mammals, including humans, do not regenerate hair cells.

The second project will examine whether epigenetic DNA modification (the inactivation of genes by chemical changes to the DNA) is why mice supporting cells are unable to transform into hair cells after damage to the ear. Our existing data suggests this is the case, and so a strategy for hearing restoration may involve the reversal of these epigenetic modifications.

The first project will allow us to identify the genes involved, and the second project will help us understand how to effectively manipulate those genes despite their DNA modifications—and to biologically restore hearing.

The consortium approach funded by HHF provides a unique opportunity; the collaboration of 15 outstanding hearing investigators will lead to results far more quickly than traditional projects that rely on a single investigator. All HRP investigators plan projects and interpret data arising from them, allowing us to collectively utilize our 200-plus years of experience we have studying the ear.

HHF has been able to increase HRP funding for 2017 compared with 2016—for this I am grateful. However, there are several research needs unmet. Increased funding levels would speed our deeper understanding of hair cell regeneration, which will ultimately lead us to find therapies to treat human hearing loss and tinnitus.

Most of all, we are looking to add additional scientists to HRP labs to increase productivity and significantly accelerate research progress. There is also an urgent need for more “bioinformatics” scientists to thoroughly examine our data and identify common threads buried deep within our results. In addition, the HRP has research projects that have been placed on hold until funding is found for them.

We are excited about the coming year’s planned research, and eagerly await the results. On behalf of myself and the other scientists who make up the HRP, I thank you for your investment and interest in our work. I look forward to giving you further updates.

HRP scientific director Peter Barr-Gillespie, Ph.D., is the associate vice president for Basic Research and a professor of otolaryngology at the Oregon Hearing Research Center, and a senior scientist at the Vollum Institute, all at Oregon Health & Science University. 

We need your help in funding the exciting work of hearing and balance scientists.

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New Player Identified in Hair Cell Development

By Betty Zou, Sunnybrook Research Institute

Sensory hair cells (red) and supporting cells (green) are intricately organized in the developed cochlea. Supporting cells have high levels of the Kremen1 protein, which is stained with a green fluorescent marker here. [Image courtesy of Dr. Alain Dabdoub]

Sensory hair cells (red) and supporting cells (green) are intricately organized in the developed cochlea. Supporting cells have high levels of the Kremen1 protein, which is stained with a green fluorescent marker here. [Image courtesy of Dr. Alain Dabdoub]

There are roughly 37.2 trillion cells in the human body, each of which can be categorized into one of about 200 different types. What’s remarkable about this immense number and diversity of cells is that they all came from a microscopic cluster that comprises the embryo. Many of these early progenitor cells start out the same, but they receive different programming instructions along the way that enable them to replicate and differentiate to form various tissues and organs.



Signalling pathways are cellular communication systems that govern whether a cell keeps dividing or stops, where it goes and, ultimately, what it becomes. One such pathway is Wnt (pronounced “wint”) signalling, a group of signal transmission networks that play a critical role in embryonic development. Dr. Alain Dabdoub, a scientist in Biological Sciences at Sunnybrook Research Institute, is studying how Wnt signalling affects inner ear development and hearing. A new study by his team has shown for the first time that Kremen1, a poorly understood member of the Wnt network, plays a direct role in the formation of the cochlea, a spiral-shaped auditory sensory organ in the inner ear.

“We know that initially at the very early stages [of development], Wnt signalling pushes cells to proliferate,” says Dabdoub. “Then division stops and cell differentiation occurs. We’re trying to find out what promotes this high level of Wnt and also what decreases it.”

Kremen1 is a protein that sits on the cell surface where it receives and transmits signals to the cellular machinery inside. Previous studies have shown that it blocks Wnt signalling, so Dabdoub and his team decided to investigate whether Kremen1 is involved in cell differentiation in the cochlea.

The researchers found that at an early embryonic stage Kremen1 was present in the precursor cells that give rise to hair cells and supporting cells. Shortly thereafter, Kremen1 was only found in the supporting cells that surround hair cells. When the researchers forced the precursor cells to overproduce Kremen1, fewer of them went on to become hair cells and more became supporting cells. In contrast, knocking down levels of Kremen1 resulted in more hair cells. The results were published in August 2016 in the journal Scientific Reports.

The cochlea contains tens of thousands of hair cells, which have hair bundles on their surface to detect and amplify sound. In mammals, when these cells are damaged or destroyed, they are not replaced and hearing loss results. Supporting cells, on the other hand, remain abundant during an individual’s lifetime and do not appear to be affected by the insults that batter hair cells.

Dabdoub’s research seeks to understand how the cochlea and hair cells form, as well as how these sensory cells can be replenished to restore hearing. “If you think about regeneration, where are the cells that you’re going to regenerate coming from?” he says.

The survival of supporting cells makes them excellent candidates from which to regrow hair cells, but they must first replicate to ensure there are enough to maintain a stable number of supporting cells and form new hair cells. Dabdoub thinks that exploiting the proliferation-enhancing properties of Wnt signalling will help achieve this. His finding that Kremen1 plays an important role in cell fate decisions in the cochlea will be critical to future efforts to regenerate hair cells. “This is a molecule that we should keep an eye on as we work towards regeneration,” he says.

Funding for this study came from the Hearing Health Foundation’s Hearing Restoration Project, Koerner Foundation and Sunnybrook Hearing Regeneration Initiative.

This blog was reposted with the permission of Sunnybrook Research Institute.
 

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Are Hair Cell Regeneration Genes Blocked?

By Yishane Lee

On March 8, 2016, Hearing Health Foundation hosted a live-video research briefing, as part of an ongoing effort to provide regular updates on our research programs and progress. Through these briefings, our goal is for our attendees to learn new information and achieve a greater understanding of hearing loss, prevention, and to o develop effective therapies for hearing loss and tinnitus.

Peter Barr-Gillespie, Ph.D., the scientific director of the Hearing Restoration Project (HRP), began the webinar with announcing the newest HRP consortium member, Ronna Hertzano, M.D., Ph.D., from the University of Maryland. Ronna is a clinician as well as a research scientist, a rare combination and an asset for the HRP. She also developed a bioinformatics platform, gEAR, that the HRP is using to efficiently compare large, complex genetic datasets between species.

Dr. Barr-Gillespie went on to outline a year in the life of the HRP—how the investigators collaborate, discuss, and develop research projects. He then provided an overview of a currently funded project focused on examining whether genes can be manipulated to overcome a block to hair cell regeneration in mammals, including humans. The advancements in technologies, such as CRISPR gene modification, provides the HRP with the ability to study hair cell regeneration in different species and at a level of detail and manipulation unheard of before.

We invite you to watch the video with captioning, or read the presentation with summary notes. We are excited to share this discussion of the HRP’s progress to date and our plans for 2016 and beyond.

 

Your Support Is Needed!

Hair cell regeneration is a plausible goal for eventual treatment of hearing and balance disorders.

The question is not if we will regenerate hair cells in humans, but when.  

However, we need your support to continue this vital research and find a cure!

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Spotlight On: Stefan Heller, Ph.D.

By Stefan Heller, Ph.D.

CURRENT INSTITUTION: 

Stanford University

EDUCATION:

Studied Biology at the University of Mainz, Germany

Ph.D. at the Max Planck Institute for Brain Research in Frankfurt, Germany

Postdoc at The Rockefeller University, New York, NY

Heller_Retreat_3_crop.jpg

We are grateful for your interest in Hearing Health Foundation (HHF). Through Spotlight On, HHF aims to connect our supporters and constituents to its Hearing Restoration Project (HRP) consortium researchers. We hope this feature helps you get to know the life and work of the leading researchers working collaboratively in pursuit of a cure for hearing loss and tinnitus

What is your area of focus? 

My laboratory seeks to understand how a small patch of embryonic cells forms the inner ear, particularly the sensory hair cells of the cochlea and vestibular organs. We are also very interested in the biology of supporting cells, which in chickens have the ability to regenerate lost hair cells. Another research interest of ours is the use of stem cells to generate inner ear cells “from scratch.”

Why did you decide to pursue scientific research? 

As a kid, I convinced my parents to buy me a chemistry lab kit. On numerous occasions the basement needed to be evacuated because of nasty fumes that filled the room. This experience probably gave me an edge when studying science in school, where I had encouraging teachers who inspired interest in neuroscience and genetics. I realized that science provides an endless playing field to connect basic discoveries to the development of useful applications.

Why hearing research? 

Serendipity! My Ph.D. thesis focused on how nerve cells are affected by so-called neurotrophic factors. This field of research was popular in the early 1990s because it promised to lead to cures for disorders such as ALS, Parkinson’s, and Alzheimer’s. With many researchers already working on finding cures for these conditions, I believed a cure was right around the corner and I’d be out of a job quickly. So I looked for a new challenge and found the laboratory of Jim Hudspeth, an HHF Emerging Research Grantee in 1979 and 1980, whose research focuses on inner ear hair cells. Five minutes with Jim and I was hooked.

What do you enjoy doing when not in the lab?

I enjoy renovating our family’s 65-year-old midcentury modern house one step at a time. After 10 years, I am about half done. I also enjoy camping trips with my wife and dog; we like hiking and being off the grid to recharge our batteries.

If you weren’t a scientist, what would you have done?

I’ve always felt that research is the best fit for me. I like modern architecture, and although I am not necessarily talented in drawing, I might have liked to do something in that field.

What do you find to be most inspirational?

Interacting with creative people and living in the Bay Area, a region where innovation is cherished and rewarded. All of my mentors have one important trait in common, and that is generosity. They were generous in volunteering their time to discuss wild ideas and scientific problems, giving me resources to explore and experiment. I try to apply this principle to my laboratory group as well.

Hearing Restoration Project

What has been a highlight from the HRP consortium collaboration?

The most valuable aspect of the HRP is that we get together as a group and talk about experiments, approaches, and the problems at hand. There are not many researchers focusing on hearing restoration, so bringing them together frequently is very helpful. We meet twice a year in person and once a month via conference calls, which is optimal for fruitful discussions. Having unlimited access to this talented group brings a lot of value.

How has the collaborative effort helped your research?

Without the HRP, I would not have started to focus on chicken hair cell regeneration. The collaborative approach, made possible through funding from HHF, has helped us to implement novel tools and the latest technology. Combining resources and technologies strengthens our research and expedites projects that help us reach our goal to find a cure for human hearing loss and tinnitus.

What do you hope to have happen with the HRP over the next year? Two years? Five years?

I envision that we will have started to fill in some of these missing components and that we have identified ways to reactivate hair cell regeneration in the mammalian cochlea. I also hope that people connected to the cause, such as individuals living with hearing loss and HHF’s generous supporters, remain patient, because science takes time in order to reach a desired result. We are working on a very complicated problem, and with each new discovery we find new roadblocks that need to be eliminated. I dream of the day when these roadblocks are all gone and we do not encounter new ones. This will be the day we realistically can expect a cure.

What is needed to help make HRP goals happen?

Ongoing funding. HHF is currently supporting research projects at a dozen laboratories, and increased funding per laboratory would allow for even more research to be conducted. HRP researchers benefit from sharing knowledge and small collaborations, but I feel that large-scale concerted efforts and sustained funding are essential to make the HRP’s goals a reality. Hopefully one of the currently funded, small-scale, concerted collaborations will lead to a “eureka” moment that will allow us to leapfrog directly to testing new drugs. Finally, patience is a must! Combined, all of the laboratories working on finding cures for hearing loss and tinnitus totals fewer than 500 researchers worldwide. It is a small field with limited resources, but I am very encouraged about the progress we’ve made so far.

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

 
 
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Best Supporting Actors - In Your Ears?

By the University of Michigan Health System

This microscopic view of cells deep within the ear of a newborn mouse show in red and blue the supporting cells that surround the hair cells (green) that send sound signals to the brain. New research shows that the supporting cells can regenerate if damaged in the first days of life, allowing hearing to develop normally. This gives new clues for potential ways to restore hearing.     Credit: Guoqiang Wan, Univ. of Michigan

This microscopic view of cells deep within the ear of a newborn mouse show in red and blue the supporting cells that surround the hair cells (green) that send sound signals to the brain. New research shows that the supporting cells can regenerate if damaged in the first days of life, allowing hearing to develop normally. This gives new clues for potential ways to restore hearing.


Credit: Guoqiang Wan, Univ. of Michigan

There’s a cast of characters deep inside your ears -- many kinds of tiny cells working together to allow you to hear. The lead actors, called hair cells, play the crucial role in carrying sound signals to the brain.

But new research shows that when it comes to restoring lost hearing ability, the spotlight may fall on some of the ear’s supporting actors – and their understudies.

In a new paper published online first by the Proceedings of the National Academy of Sciences, researchers from the University of Michigan Medical SchoolSt. Jude Children’s Research Hospital and colleagues report the results of in-depth studies of these cells, fittingly called supporting cells.  

The research shows that damage to the supporting cells in the mature mouse results in the loss of hair cells and profound deafness. But the big surprise of this study was that if supporting cells are lost in the newborn mouse, the ear rapidly regenerates new supporting cells – resulting in complete preservation of hearing. This remarkable regeneration resulted from cells from an adjacent structure moving in and transforming into full-fledged supporting cells. 

It was as if a supporting actor couldn’t perform, and his young understudy stepped in suddenly to carry on the performance and support the lead actor -- with award-winning results.

The finding not only shows that deafness can result from loss of supporting cells -- it reveals a previously unknown ability to regenerate supporting cells that’s present only for a few days after birth in the mice.

If scientists can determine what’s going on inside these cells, they might be able to harness it to find new approaches to regenerating auditory cells and restoring hearing in humans of all ages.

Senior author and U-M Kresge Hearing Research Institute director Gabriel Corfas, Ph.D., says the research shows that supporting cells play a more critical role in hearing than they get credit for.

In fact, he says, efforts to restore hearing by making new hair cells out of supporting cells may fail, unless researchers also work to replace the supporting cells. “We had known that losing hair cells results in deafness, and there has been an effort to find a way to regenerated these specialized cells. One idea has been to induce supporting cells to become hair cells. Now we discover that losing supporting cells kills hair cells as well,” he explains.

“And now, we’ve found that there’s an intrinsic regenerative potential in the very early days of life that we could harness as we work to cure deafness,” continues Corfas, who is a professor in the U-M Department of Otolaryngology. “This is relevant to many forms of inherited and congenital deafness, and hearing loss due to age and noise exposure. If we can identify the molecules that are responsible for this regeneration, we may be able to turn back the clock inside these ears and regenerate lost cells.”

In the study, the “understudy” supporting cells found in a structure called the greater epithelial ridge transformed into full-fledged supporting cells after the researchers destroyed the mice’s own supporting cells with a precisely targeted toxin that didn’t affect hair cells. The new cells differentiated into the kinds that had been lost, called inner border cells and inner phalangeal cells.

“Hair cell loss can be a consequence of supporting cell dysfunctional or loss, suggesting that in many cases deafness could be primarily a supporting cell disease,” says Corfas. “Understanding the mechanisms that underlie these processes should help in the development of regenerative medicine strategies to treat deafness and vestibular disorders.”

Making sure that the inner ear has enough supporting cells, which themselves can transform into hair cells, will be a critical upstream step of any regenerative medicine approaches, he says.

Corfas and his colleagues continue to study the phenomenon, and hope to find drugs that can trigger the same regenerative powers that they saw in the newborn mice.

The research was a partnership between Corfas’ team at U-M and that of Jian Zuo, Ph.D., of St. Jude, and the two share senior authorship. Marcia M. Mellado Lagarde, Ph.D. of St. Jude and Guoqiang Wan, Ph.D., of U-M are co-first authors. Additional authors are LingLi Zhang of St. Jude, Corfas’ former colleagues at Harvard University Angelica R. Gigliello and John J. McInnis; and Yingxin Zhang and Dwight Bergles, both of Johns Hopkins University.

The research was funded by a Sir Henry Wellcome Fellowship, a Hearing Health Foundation Emerging Research Grant, the Boston Children’s Hospital Otolaryngology Foundation, National Institutes of Health grants DC004820, HD18655, DC006471, and CA21765; Office of Naval Research Grants N000140911014, N000141210191, and N000141210775, and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital.

The above post is reprinted from materials provided by University of Michigan Health System

  We need your help in funding the exciting work of hearing and balance scientists. 

To donate today to Hearing Health Foundation and support groundbreaking research, visit hhf.org/name-a-grant.

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Ask the Scientist: Gene Therapies and Hearing

By Peter G. Barr-Gillespie, Ph.D.

A DNA double helix    National Human Genome Research Institute

A DNA double helix

National Human Genome Research Institute

Recently, Hearing Health Foundation (HHF) has received several questions regarding the Reuters report on gene therapies for hearing. There are two separate but related topics raised in this article. As the scientific research director of HHF’s Hearing Restoration Project, which since 2011 has been uncovering concrete discoveries toward a biologic cure for hearing loss and tinnitus, I want talk about each individually, and then discuss what I interpret they mean together.

 

The article first presents the Science Translational Medicine paper from Jeffrey Holt’s lab. This is very much a proof-of-principle report, focused on an animal model and using a time for delivery of the corrected gene that is extremely early in development (equivalent to a 5-to-6-month-old human fetus). It is important to point out that their strategy will only correct one type of genetic hearing loss and genetic hearing loss from mutations in other genes will require related but different strategies. Nevertheless, this is an exciting example of modeling gene therapy in animals, and represents a logical progression toward that goal in humans.

The article then moves on to reference the Novartis trial. For this trial, they are using a similar technical strategy, viral delivery of a gene, but they are targeting people—those who have lost their hearing through non-genetic means, such as noise damage, aging, or infections. The gene they are delivering, known as ATOH1, may stimulate production of new hair cells; it is a gene that is essential for formation of hair cells during development, and in some experimental animal models, delivery of the gene can lead to production of a few hair cells in adult ears.

That said, many people who I have talked to in the field who work with experimental models of hair cell formation using ATOH1, including members of our Hearing Restoration Project consortium, believe that this trial is premature. By and large, the animal models do not support the trial; most suggest that there will be few hair cells formed and little hearing restored. While we can hope for a little bit of hearing recovery, we are concerned about toxic responses to the gene delivery using viruses. Personally, while I think it would be truly fantastic if the Novartis trial works, at this moment in time I don’t think the rewards yet outweigh the considerable risks being imposed on a human (include safety during the procedure and potential side effects afterward).

Still, the Novartis trial will tell us about the safety of viral delivery into the ears of humans, and knowing that is critically important. I think the most likely outcome is that we will learn whether the strategy the Novartis trial used to deliver the gene is safe. Unfortunately, if we don’t see improved hearing, we won’t know why—did the gene not get to the right place, or does it just not work?

Technical aspects of gene delivery are what ties together the Novartis work and the Holt lab work. Both use viruses for delivering genes, and together the results from these and others will let us know, from a procedural standpoint, how we can deliver genes to the ear. I think it is unlikely that delivering just ATOH1 will do the trick of restoring hearing; it may be that we need to deliver other genes or to use drugs to overcome the block we see to making new hair cells.

So while these are exciting reports to hear about, especially that Novartis is actually carrying out a trial in humans, it is still premature to think that this is going to be a viable strategy for restoring hearing. This is why Hearing Health Foundation's Hearing Restoration Project is doing everything possible to accelerate the pace of its research.

Hair cell regeneration is a plausible goal for the treatment of hearing and balance disorders. The question is not if we will regenerate hair cells in humans, but when. Your financial support will help to ensure we can continue this vital research and find a cure in our lifetime! Please help us accelerate the pace of hearing and balance research and donate today. Your HELP is OUR hope!

If you have any questions about this research or our progress toward a cure for hearing loss and tinnitus, please contact Hearing Health Foundation at info@hhf.org.

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Taking Hair Cell Regeneration Down a Notch

By Andy Groves

Hearing Restoration Project (HRP) consortium scientists, Andy Groves and Stefan Heller had their research published in Frontiers in Cellular Neuroscience on March 31, 2015. Below is a summary of their research:

Sensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells.

During the development of the inner ear, newly-born hair cells send signals to their neighbors that instruct them to not become hair cells, but to become supporting cells instead. Hair cells are the mechanosensitive cells of the ear. Supporting cells surround them and as their name implies, physically support them and help regulate some of the properties of hair cells. One of these signals is an evolutionarily ancient pathway, the Notch signaling pathway. We and others have shown that if you block the Notch signaling pathway in the cochlea or balance organs of young mice, the supporting cells no longer get the message to stay as supporting cells, and instead they transform into hair cells. This process also happens during hair cell regeneration in birds - supporting cells transform into hair cells, which then send a Notch signal to their neighbors and prevent too many hair cells from being formed.

These observations suggest that it might be possible to block Notch signaling in mature, deafened animals as a means of getting new hair cells to form. We performed a simple experiment to test this in progressively older and older animals. To our surprise, we found that once mice are more than a week old, blocking Notch signaling has no effect on the cochlea any more, and no new hair cells are made.  We showed that this was due in part to components of the Notch signaling pathway being switched off in the ear as the animals get older. Viewed this way, the Notch signaling pathway can be thought of as a “Scaffold” - it is used to allow the cochlea to be built in the first place, but is then dismantled once the cochlea becomes functional.

What does this mean? It suggests that inhibiting Notch signaling alone is unlikely to be an effective means of hair cell regeneration in mammals. It is possible that other factors will be required, and some HRP members are busy testing these other pathways right now. It will also be of great interest to understand HOW the Notch pathway is dismantled with age, whether we can exploit this in future therapies.

Read more about this research proposal here: http://hearinghealthfoundation.org/hrp-consortium-projects-groves-segil-stone.

This work was supported by Department of Defense Grant DODW81XWH-11-2-004(AKG) and Hearing Restoration Project consortium grants from the Hearing Health Foundation (AKG and SH), NIH grant DC004563 (SH), NIH grant P30DC010363 (SH, JSO), and NIHR01DC014450 (JSO).

Hair cell regeneration is a plausible goal for the treatment of hearing and balance disorders. The question is not if we will regenerate hair cells in humans, but when. Your financial support will help to ensure we can continue this vital research and find a cure in our lifetime! Please help us accelerate the pace of hearing and balance research and donate today. Your HELP is OUR hope!

If you have any questions about this research or our progress toward a cure for hearing loss and tinnitus, please contact Hearing Health Foundation at info@hhf.org.

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Gene Discoveries May Lead to Regeneration of Cells Needed for Hearing

By Jeffrey Norris

The researchers identified patterns of gene expression that may determine whether the ear’s inner pillar cells can give rise to new hair cells, which are key to hearing.

School of Medicine scientists have discovered biological mechanisms that appear to play a role in the regeneration of cells in the inner ear.

Over a lifetime, these cells often are damaged or die due to oxidative stress, excessive noise exposure or toxic drugs. The accumulated loss can significantly compromise hearing. Nearly one in four people ages 65-74, and half who are 75 or older, are candidates for hearing aids because of disabling hearing loss.

The discoveries could lead to new ways of evaluating, in animal models, experimental drug treatments intended to prevent hearing loss or restore hearing, and might even lead to methods for regenerating vital cells that have been lost, said Stefan Heller, PhD, professor of otolaryngology.

A paper describing the findings, as well as new methods to quickly link changes in cell function during development to molecular changes within cells, was published June 9 in Cell Reports. Heller is the senior author of the paper. Postdoctoral scholars Jöerg Waldhaus, PhD, and Robert Durruthy-Durruthy, PhD, share the lead authorship.

Discoveries by Stefan Heller and his colleagues could lead to new ways of evaluating, in animal models, experimental drug treatments intended to prevent hearing loss or restore hearing. -  Steve Fisch

Discoveries by Stefan Heller and his colleagues could lead to new ways of evaluating, in animal models, experimental drug treatments intended to prevent hearing loss or restore hearing. - Steve Fisch

Sound waves striking the eardrum cause vibrations that are transmitted through tiny bones in the middle ear to fluid within the snail-shell-shaped cochlea of the inner ear. Specialized cochlear cells in a region called the organ of Corti use hairlike sensors to detect the vibrations in cochlear fluid and then trigger nerve signals that are sent to the brain.

“Compared to other senses, we know very little about how hearing works,” Heller said. “The cells are rare. We have to crack open a bone to get to them. They perish quickly, so we must work fast.” There are 120 million retinal cells in a mouse eye, Heller said, but only 3,200 hair cells in a mouse ear.

By using new techniques to rapidly and deeply probe individual cells, Heller’s team has begun to close the knowledge gap.

Molecular mysteries

Many of the biophysical properties of hair cells are understood. Different hair cells along the cochlear spiral are tuned to respond to distinct ranges of sound frequency based on differences in their electrical properties. Frequency is encoded by the place and the properties of the cells’ locations in the cochlea. This understanding has led to the development of cochlear implants to restore hearing in deaf people.

However, little is known about the molecular biology that determines how hair cells develop at specific locations and how different electrical properties arise among hair cells specialized to detect different frequencies. This makes it difficult for scientists to envision strategies to regenerate the specialized cells or to prevent their death, particularly in the high-frequency region of the cochlea, where cells are more susceptible to injury.

Once hair cells die in a mature mammal, they are not replaced. But scientists have recently determined that a supporting cell type, called the inner pillar cell, has the potential to regenerate hair cells in newborn mice.

In its new study of 2-day-old mice, Heller’s lab team measured the activity of 192 genes. The researchers determined which genes were turned on, or “expressed,” in each of 808 hair cells and supporting cells from either the apex or base of the organ of Corti. They quantified this gene expression by measuring the amount of RNA produced from each gene.

The researchers identified patterns of gene expression that may determine whether inner pillar cells can give rise to new hair cells. Similarly, they discovered gradual changes in the expression of specific genes across cells that span the organ of Corti from its base to its apex that may be crucial for the establishment and maintenance of a population of hair cells that responds to a range of sound frequencies.

Crunching the data

Using powerful number-crunching software to analyze the large amount of genetic data, Heller’s lab team accurately identified the two known types of hair cells and the seven known types of supporting cells and created a computer-generated map of their locations within the organ of Corti. They did this using only the genetic data, but then used other previously known DNA sequences to independently verify the accuracy of the cell identification and mapping.

The strategy the researchers used to predict the spatial location of cells within the organ of Corti from gene-expression data also should prove useful to biologists who study other types of cells in different organs, Heller said.

Rapid advances in single-cell gene-expression analysis are likely to supplant a standard technique called in-situ hybridization, according to Heller. The standard technique relies on labeled genetic probes to target individual genes one by one in order to identify specific cell types. The new approach of measuring hundreds of genes in parallel and reconstructing the organs in the computer appears to be more accurate and powerful.

“Molecular gradients play a key role in developmental biology, but in the past researchers depended on identifying gradients in one molecule at a time,” Heller said. “With these new techniques, we are identifying cells that, for example, have molecular characteristics of stem cells, by analyzing the expression of many genes all at once, and we know precisely where they are located.”

The research was funded by the National Institutes of Health (grants DC006167 and DC012250), the Stanford Initiative to Cure Hearing Loss and Hearing Health Foundation’s Hearing Restoration Project.

Stanford’s Department of Otolaryngology-Head & Neck Surgery also supported the work.

Republished with permission from the Stanford School of Medicine's Office of Communication & Public Affairs.

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Hearing Health Foundation at Partnering for Cures 2014

By Pallavi Bharadwaj

Convened by FasterCures, the Washington, D.C.-based center of the Milken Institute, the conference will bring together nearly 1,000 medical research leaders, investors and decision-makers to forge the collaborations needed to speed and improve outcomes-driven R&D. The ongoing promise of hair-cell regeneration is closer to reality than ever.

Hearing Health Foundation’s Hearing Restoring Project consortium has identified major roadblocks that have stymied the field, and has designed rational approaches to overcome these barriers.

Partnering for Cures is designed to facilitate informed investments and cultivate relationships, adapting the outcomes-oriented approach of investor conferences, and building on the networking opportunities at industry partnering meetings. In addition to innovator presentations, it also features panels that spotlight solutions to long-standing challenges in medical research.

 “We are very pleased to be present and participate in this conference. It is a unique opportunity to raise visibility for hearing loss and the path to a cure among an important audience.” says Claire Schultz, CEO HHF.

Hearing Health Foundation is one of 30 innovators presenting their cross-sector research collaboration to potential partners and funders at the conference.  Selected through a competitive proposal process, each partnership is aimed at reducing the time and cost of getting new medical solutions from discovery to patients.

“These collaborations address some of the thorniest issues in medical research using models that can be scaled and translated across diseases,” said FasterCures’ Executive Director Margaret Anderson.

“From re-imagining clinical trial infrastructure to improving and expanding data sharing, to creating the tools and resources needed to translate basic science into cures, they are accelerating the path from lab to market for novel – and needed – therapies.”

For more information and to register for the conference, go to www.partneringforcures.org

To know more on HHF’s Hearing Restoration Project presentation at Parterning for Cures 2014, please click here

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