Tag Archives: Hair cells

Permanent hearing loss may not be so permanent after all — in mice, for now

Credit: Pixabay.

Once we damage sensory cells in the inner ear, either due to some accident or simply growing old, this damage is irreversible, leading to hearing loss. However, there may be a way to regenerate some of these cells. In a remarkable new study, researchers at the University of Southern California have identified a molecular pathway that, when activated, may trigger the regeneration of lost sensory cells, thereby restoring hearing. Although the findings apply to mice, targeted therapy may also work on other mammals, including humans.

Approximately one in three people between the ages of 65 and 74 has hearing loss, and nearly half of those older than 75 have difficulty hearing.  The most common type is sensorineural hearing loss caused by the degradation and loss of sensory hair cells in the cochlea (the auditory part of the inner ear).

Hair cells are the sensory receptors for both the auditory system and the vestibular system in our ears — and the ears of all vertebrates. These hair-like projections play a big part in both our hearing and our balance, transforming the sound vibrations in the cochlea into electrical signals which are fed to auditory nerves and sent up to the brain.

But there’s a second type of sensory cell in the cochlea called “supporting cells”. As the name suggests, these cells play a secondary role in hearing by supporting important structural and functional processes.

Previously, scientists were stunned to find that lab mice who had suffered damage to their cochlea transformed supporting cells into hair cells through a process known as “transdifferentiation”, recovering some of their hearing. However, this only happened in mice who were only a few days old. Once they grew older, they lost this ability.

Credit: Developmental Cell.

Scientists think that humans may also possess this regenerative capacity but likely only while still developing as an embryo. By the time humans are born, this ability is probably long gone.

Starting from these observations, lead authors Litao Tao and Haoze “Vincent” Yu zoomed in on the molecular mechanisms that support transdifferentiation in mouse pups and the neonatal changes that block this process.

According to the investigation, the transdifferentiation of supporting cells is mediated by hundreds of genes that are normally turned off but which get switched on in the presence of activating molecules. Conversely, these genes can be turned off by the presence of repressive molecules. These alterations are known as “epigenetic modifications” and play a huge role in regulating gene activity and controlling the properties of the genome.

In experiments with supporting cells from newborn mouse cochleas, the scientists found that hair cell genes were suppressed by both the lack of an activating molecule, H3K27ac, and the presence of the repressive molecule, H3K27me3. However, juggling these molecules alone is not enough to convert supportive cells into hair cells. An additional molecule H3K4me1 primes these genes for activation and hair cell development.

Due to the aging process, the H3K4me1 priming molecule is lost. But when the scientists introduced a drug that prevents the loss of H3K4me1, the supporting cells stayed primed for transdifferentiation despite the advanced age of the cells, as reported in the journal Developmental Cell.

“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing,” said Segil in a statement. “Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”

Elsewhere, researchers at the University of Rochester tweaked a group of epidermal growth factor (EGF) receptors that are known to be responsible for activating support cells in the auditory organs of birds. Through a combination of drugs originally developed to stimulate stem cell activity and genetic modification, they were able to activate the same molecular pathway in mice. This led to the proliferation of cochlear support cells, triggering neighboring stem cells to develop into new sensory hair cells.

Repairing hearing is a complex problem. Not only do hair cells require regeneration, but they also have to connect properly to the necessary network of neurons. But these promising studies show that at some time in the future, growing old may not necessarily mean bad hearing anymore. 

Inner ear diagram.

We finally found the protein that turns sound and balance into electrical signals

Researchers have pinpointed the protein that turns sound and head movement into nerve signals for the brain.

Inner ear diagram.

An embroidered diagram of the inner ear.
Image credits Hey Paul Studios.

A team from the Harvard Medical School believe they’ve ended a 40-year-long search for the protein that allows us to hear and stay upright. Nestled in the inner year, this molecule turns sound and movements of the head into electrical signals — it is, in effect, what translates them into a language our brain can understand.

Ear-round signaling

The team points to TMC1 (Transmembrane channel-like protein 1), a protein discovered in 2002, as being the elusive molecule researchers have been looking for. TMC1 folds in on itself in such a way as to form a sound-and-motion-activated pore. In effect, it acts much like a microphone: the protein turns pressure waves into electronic signals, a process known as ‘auditory transduction’. These are then fed to the brain, where they’re recreated into sound and help us maintain balance.

The findings come to fill in a gap in our understanding of how hair cells in the inner ear convert sound and movement into signals for the nervous system.

“The search for this sensor protein has led to numerous dead ends, but we think this discovery ends the quest,” said David Corey, Bertarelli Professor of Translational Medical Science at Harvard and co-senior author on the study.

“It is, indeed, the gatekeeper of hearing,” says co-senior author Jeffrey Holt, a Harvard Medical School professor of otolaryngology and neurology at Boston Children’s Hospital.

The team hopes that their findings can lead to precision-targeted therapy for hearing loss associated with malformed or missing TMC1 proteins.

Hearing is one of the very few senses whose molecular converters remained unknown. This was, in part, due to the position of the inner ear. Nestled in the skull, the densest bone in the body, this organ is hard to reach. To further complicate matters, it also houses relatively few sensory cells that can be retrieved, dissected, and imaged. Our inner ear houses roughly 16,000 auditory cells — a human retina, by contrast, boasts over a hundred million sensory cells.

The team’s research was based on the discovery of the TMC1 gene in 2002. Back in 2011, a team led by Holt proved that TMC1 was required for transduction, but whether it was is a key player or just a supporting actor in the process. So, naturally, it sparked a heated debate among researchers.

Step-by-step process

The current paper aimed to put this debate to rest. In an initial set of experiments, the team found that TCM1 proteins clump together in pairs to form ion channels (basically pores). It was quite a surprising discovery, as most ion channels are built from three to seven proteins, the team explains. However, this unusual pairing also helped the researchers make sense the protein’s structure.

The second step was to map out the protein’s 3D structure. Computer predictive modeling, a process that works by predicting the most probable arrangement of a protein’s atoms based on comparisons with similar proteins with known structures, was used. This approach is based on the fact that a protein’s functions are dictated by its structure, i.e. its specific arrangement of amino acids.

The algorithm revealed that TMC1’s closest relative with known structure was a protein known as TMEM16, and yielded a possible amino acid model for TMC1.

Finally, the team set out to confirm whether the computer model was onto something or not by using mouse models. The team substituted 17 amino acids — one at a time — in the hair cells of living mice and then noted how each alteration changed the cell’s ability to pick up on sound, movement, or the flow of ions (i.e. electrical signals).

Eleven of the substitutions altered the flow of ions, five of them having a dramatic effect (reducing flow by up to 80%), the team reports. One substitution blocked the flow of calcium ions completely.

“Hair cells, like car engines, are complex machines that need to be studied as they are running,” says Corey. “You can’t figure out how a piston or a spark plug works by itself. You have to modify the part, put it back in the engine and then gauge its effect on performance.”

Another strong indicator that TMC1 is central to hearing is that it’s found in all vertebrates — mammals, birds, fish, amphibians, and reptiles.

“The fact that evolution has conserved this protein across all vertebrate species underscores how critical it is for survival,” Holt said.

The paper “TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells” has been published in the journal Neuron.