Their experiments revealed a class of DNA control elements known as “enhancers” that, after injury, amplify the production of a protein called ATOH1, which in turn induces a suite of genes required to make sensory cells of the inner ear.
Mouse Studies Tune Into Hearing Regeneration
In the non-sensory supporting cells of the inner ear, key genes required for conversion to sensory cells are shut off through a process known as epigenetic silencing. By studying how the genes are shut off, we begin to understand how we might turn them back on to regenerate hearing.
Inner Ear Cell Types Between Fish and Mammals Show Similarities
The similarities of inner ear cell type composition between fish and mammals validate the zebrafish as a relevant model for understanding inner ear-specific hair cell function and regeneration.
A Common Ancestor for Cells Involved in Hearing and Touch
The sensory cells in the inner ear and the touch receptors in the skin actually have a lot in common, according to a new study from the University of Southern California (USC) Stem Cell laboratory of Neil Segil, Ph.D., published in the Proceedings of the National Academy of the Sciences.
The Latent Regenerative Potential of the Inner Ear
Scientists from the laboratory of Neil Segil, Ph.D., have identified a natural barrier to the regeneration of the inner ear’s sensory cells, which are lost in hearing and balance disorders. Overcoming this barrier may be a first step in returning inner ear cells to a newborn-like state that’s primed for regeneration
Hearing Restoration Project Plans Announced for 2020–21
Hearing loss occurs when sensory hair cells of the inner ear (cochlea) are damaged or die. The goal of the Hearing Restoration Project (HRP) is to develop therapeutic methods to convert the cells that remain after damage into new, completely functional sensory hair cells, restoring hearing. We know that in most species—but not mammals, like humans and mice—hair cells robustly regenerate on their own after damage to the auditory system.
USC Stem Cell Study Shows When to Quit “Yapping”
It turns out that to hear a person yapping, you need a protein called Yap. Working as part of what is known as the Yap/Tead complex, this important protein sends signals to the hearing organ to attain the correct size during embryonic development, according to a new study published in the Proceedings of the National Academy of the Sciences (PNAS) from the USC Stem Cell laboratory of Neil Segil.
Filling in the Gaps
The annual meeting of Hearing Health Foundation’s (HHF) Hearing Restoration Project (HRP) was held in Seattle Dec. 12–14, 2019. As always, we use this extended in-person meeting to discuss in detail the progress of the consortium over the past year and to develop our plan for the upcoming year.
Watch This New Captioned Video from Our Hearing Restoration Project (HRP)
In October, the Scientific Director of Hearing Health Foundation (HHF)’s Hearing Restoration Project (HRP), Peter Barr-Gillespie, Ph.D., was the keynote speaker of The New York Academy of Sciences (NYAS)’s “Hearing Restoration and Hair Cell Regeneration,” a symposium to connect internationally recognized hearing loss experts from academia, industry, government, and nonprofit organizations.
On a Data-Driven Mission
By Peter G. Barr-Gillespie, Ph.D.
The annual meeting of Hearing Health Foundation’s (HHF) Hearing Restoration Project was held in Seattle November 11-12, 2018. We used this meeting to update one another on recent progress on HHF-funded projects, discuss in detail the implications of new data, evaluate the directions of ongoing projects, and plan for the next funding period.
As you may recall, in November 2016 the Hearing Restoration Project (HRP) made a deliberate turn toward funding only the highest-impact science that our group leads the world in researching—we have termed this the “Seattle Plan.” We therefore devoted a substantial portion of our efforts to cross-species comparisons that contrast molecular responses to inner ear sensory hair cell damage in species that regenerate their hair cells, especially chickens and fish, with responses in mice, which like other mammals do not regenerate their hair cells. We also have been examining the “epigenetic” structure of key genes in the mouse, as one hypothesis is that epigenetic modifications of the DNA—that is, the inactivation of genes through chemical changes to the DNA—causes mouse (and human) cells of the cochlea to no longer respond to hair cell damage by regenerating hair cells.
Avian and mammal supporting cell subtypes differ, but Stefan Heller, Ph.D., and team are investigating if an evolutionary homogenous equivalent exists in the organ of Corti, and if this knowledge could be used for hair cell regeneration. Credit: Chris Gralapp / Otolaryngology Head and Neck Surgery (OHNS) - Stanford University School of Medicine
I am happy to report that progress over the past two years on these two major projects has been outstanding. For the cross-species comparisons, Stefan Heller, Ph.D., and Tatjana Piotrowski, Ph.D., reported on single cell analysis of, respectively, chick and fish hair cell organs responding to damage. Using single cell analysis—isolating hundreds to thousands of individual cells and quantifying all of the protein-assembly messages they express—we can determine the molecular pathways by which hair cells are formed during development and regeneration. This approach has always been promising, but this year we have begun to reap the expected benefits, as those projects have given us an unprecedented view of hair cell formation.
The epigenetics project overseen by Neil Segil, Ph.D., has now reached maturity, and using the voluminous data acquired over the past several years his lab has shown how supporting cells (from which we intend to regenerate hair cells) change the epigenetic modification of their DNA so they no longer are able to switch on key genes used for turning them into hair cells. A topic of great interest at the meeting was that of genetic reprogramming: Can we use genes (like transcription factors, proteins that control the transfer of genetic information) or small molecules (which often can be taken orally and still reach their targets) to overcome the epigenetic modification and push supporting cells to turn into hair cells? Preliminary results from Segil’s lab and from others in the field make us optimistic that the reprogramming approach will eventually be part of a regeneration strategy.
We also heard from Seth Ament, Ph.D., a bioinformatics expert we recently recruited to the HRP to explicitly compare our various datasets and find the common threads between them. Ament has used gene expression data from the chick, fish, and mouse, as well as the epigenetic data from the mouse, to hypothesize which genes may be important for hair cell regeneration. As a systems biology specialist, Ament brings a fresh eye to the field of auditory science and has not only identified some of the genes we expected to be important, but new ones as well. His success nicely justifies our cross-species approach, and the bioinformatics comparisons that he has been able to achieve in his initial HRP project have been impressive.
Finally, two other Seattle Plan projects have gone well, including our data-sharing platform called the gEAR (gene Expression Analysis Resource), developed by Ronna Hertzano, M.D., Ph.D., which allows us to analyze our data privately but also to efficiently share data with the public. In addition, John Brigande, Ph.D., reported on his project developing mouse models for testing interesting new genes; his group will be adding several powerful models in the year to come.
The excitement at the meeting extended to our future plans. We agreed that the Seattle Plan was the still the proper course, and we eagerly anticipate more data and results to come from our consortium of researchers. We are truly getting a clearer picture of hair cell regeneration due to the HRP’s efforts. That said, there is a long way to go; our efforts show us how surprisingly intricate biology is, despite knowing from the start that systems like the inner ear are remarkably complex. Nature always has surprises for us, by turns dashing treasured hypotheses while revealing unexpected mechanisms. The HRP is most definitely on track for success, and all of us in the HRP sincerely thank you for your continued support.
HRP scientific director Peter G. Barr-Gillespie, Ph.D., is a professor of otolaryngology at the Oregon Hearing Research Center, a senior scientist at the Vollum Institute, and the interim senior vice president for research, all at Oregon Health & Science University. For more, see hhf.org/hrp.
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