Tag Archives: cochlea

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. 

sensory hair cells

Hearing restored in mice after hair cells were regenerated through drug

Hearing loss is a grave healthcare problem around the world, with 50 million cases in the US alone. 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). While implants and various other hearing aids can improve hearing a tad, significant improvement can not be achieved since these sensory hair cells do not regenerate for mammals. In a remarkable breakthrough moment, scientists at Massachusetts Eye and Ear and Harvard Medical School developed a drug that can regenerate sensory hair cells in mouse ears damaged by noise trauma.

Fluid movement in the inner ear (cochlea), like sound waves propagating, causes changes in tiny structures called hair cells. As these hair cells move, electrical signals from the cochlea are sent up the auditory nerve to the brain, which is then converted into information we can commonly refer to as sound. Hair cell loss comes from noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drug.

“Hair cells are the primary receptor cells for sound and are responsible for the sense of hearing,” explains senior author, Dr. Albert Edge, of Harvard Medical School and Mass. Eye and Ear. “We show that hair cells can be generated in a damaged cochlea and that hair cell replacement leads to an improvement in hearing.”

Fighting deafness

sensory hair cellsBirds or fish can regenerate their damaged or lost hair cells, however mammals can not. The researchers tested their novel drug by applying it to the cochlea of deaf mice, which had their hearing impaired from sound trauma. The drug works by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug.

After the drug was administered significant hearing improvements were observed in mice, and further observations showed that improved hearing could be traced to the areas in which supporting cells had become new hair cells. The breakthrough is the latest in a slew of research that demonstrate hearing improvements in mammals – previously, we reported how improvements in mice hearing were made after scientists injected the cochlea with nasal stem cells, hair cell regeneration in gerbils again through stem cells and gene therapy that rendered similar results in guinea pigs.

“The missing hair cells had been replaced by new hair cells after the drug treatment, and analysis of their location allowed us to correlate the improvement in hearing to the areas where the hair cells were replaced,” Dr. Edge said.

“We’re excited about these results because they are a step forward in the biology of regeneration and prove that mammalian hair cells have the capacity to regenerate,” Dr. Edge said. “With more research, we think that regeneration of hair cells opens the door to potential therapeutic applications in deafness.”

Findings were documented in the journal Science.

source: Massachusetts Eye and Ear 

Medical devices powered by your ear

Your ear is a fascinating place – seriously, that’s not some psychotic pick up line. Deep in the inner ear of mammals lies a natural battery, a place filled with ions that produces an electrical potential which drives your neural impulses. Now, a team of researchers have shown this battery can power a device without impairing hearing or creating any other problem.

The team suggested devices which could monitor the biological activity in the ear or provide hearing benefits for the impaired. In the experiments, biologists and physicists from the Massachusetts Eye and Ear Infirmary (MEEI) and the Harvard-MIT Division of Health Sciences and Technology (HST) implanted electrodes in these biological batteries of guinea pigs. Attached to the electrons there were low-power electronic devices which monitored the chemical activity inside the ear. After the devices were implanted, the guinea pigs suffered no hear issues whatsoever, and the devices were able to transmit information via wi-fi.

“In the past, people have thought that the space where the high potential is located is inaccessible for implantable devices, because potentially it’s very dangerous if you encroach on it,” Stankovic says. “We have known for 60 years that this battery exists and that it’s really important for normal hearing, but nobody has attempted to use this battery to power useful electronics.”

Indeed, altering how this extremely effective mechanism works could be devastating. The ear converts sounds (via the vibration of the air drum) into an electrochemical signal that can be processed by the brain. This biological battery is the source of the current.

Cliff Megerian, chairman of the otolaryngology department at Case Western Reserve University sees great potential in this research and believes it could tackle 3 issues: cochlear implants, diagnostics and implantable hearing aids.

“The fact that you can generate the power for a low voltage from the cochlea itself raises the possibility of using that as a power source to drive a cochlear implant,” Megerian says. “Imagine if we were able to measure that voltage in various disease states. There would potentially be a diagnostic algorithm for aberrations in that electrical output. I’m not ready to say that the present iteration of this technology is ready,” Megerian cautions. But he adds that, “If we could tap into the natural power source of the cochlea, it could potentially be a driver behind the amplification technology of the future.”

The research was published in Nature Biology

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c) SPL / Photo Researchers, Inc

Deafness cured by gene therapy

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c)  SPL / Photo Researchers, Inc

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c) SPL / Photo Researchers, Inc

A stroke of pioneering science, researchers have managed to restore hearing to a significant level in guinea pigs by using gene therapy, bolstering hope for a similar procedure to cure human deafness in the future.

The therapy works by promoting the regeneration of hair cells in the cochlea, the part of the inner ear which registers sound. These hair cells act like tiny dishes that catch infinitezimal fluid motion and transmit them into nerve signals to the brain, which we typically recognize as sound. These tiny hairs are incredibly sensitive, and it’s common for them to deteriorate or even get completely distroyed when exposed to loud sounds, certain drugs or old age, ultimately.

“It’s the first time anyone has biologically repaired the hearing of animals,” says Yehoash Raphael at the University of Michigan in Ann Arbor, Michigan, and head of the US-Japanese team that developed the technique.

For their research, the scientists first destroyed the inner-ear hair cells in guinea pigs. Then they injected a specially engineered adenovirus, the key to the treatment. This virus is completely harmless and contains a  gene called Atoh1 or Math1, which gets infused to the cells inside the scala media, the chamber where the tiny hearing hairs lye. The gene then generates a signalling molecule known to orchestrate the development of hair cells in embryos.

“The recovery of hair cells brought the treated ears to between 50% and 80% of their original hearing thresholds.”

By all means, these are incredible results. Moroever, the researchers report that hair cells were generated from other cells lined in the scala media, meaning some cells had been turned into other cells. Incredible!

The researchers hope this therapy might be used in the future on humans, at least as a complementary measure for people already using hearing aid devices. Raphael says that the next experiments in guinea pigs will focus on this combination. However, guinea pigs are far different from humans. For one, the inner-ear is nested deep inside the skull for humans, making surgery extremely difficult*, and there’s always a big chance the immune system will reject the researcher’s engineered virus. Let’s hope for the best.

The researchers’ findings were published in the journal Nature Medicine.

 *edit: in the initial draft of this article I wrote that inner-ear surgery in humans is impossible, which is a false statement. This type of procedure is difficult, but possible. Many thanks to Paul Harris for the input.