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Regenerating hair cells – another piece of the puzzle

Hair cells are crucial for our ability to hear, but we still don’t know exactly how they develop in the inner ear, or all the genes and processes that combine to make sure they work correctly. New research that we funded has shed light on how one particular gene is involved – Tracey Pollard from our research team explains more.

We fund research into the genetics and biology of hearing loss, to find the genes we need to hear, to find out what they do, and ultimately to use this knowledge to find out how to direct their activity to regenerate inner ear hearing cells, and restore hearing.

We recently funded a team of researchers led by Dr Mike Bowl at the MRC Harwell Institute here in the UK, and Dr Ronna Hertzano at the University of Maryland in the US, to investigate the role of a gene called Ikzf2 in the inner ear. What they found was that this gene appears to be crucial for outer hair cells, a specific type of sound-sensing cell in the inner ear (or cochlea), to develop and work correctly.

Outer hair cells and what they do

Hair cells are the specialist sound-sensing cells of the inner ear, so-called because of tiny extensions on the tops of the cells that look like hairs. These cells are able to detect vibrations caused by sound waves entering the inner ear.

There are two types of hair cell, called inner and outer hair cells (so-called because of where they’re found in the cochlea). Inner hair cells detect sound waves and translate this information into electrical nerve signals that then travel along the auditory (hearing) nerve to the brain, where they are interpreted and perceived as the sounds we hear.

The outer hair cells do a different job – in the simplest terms, they act as a ‘volume control’ (in technical terms, the cochlear amplifier), allowing the inner ear to detect much quieter sounds than the inner hair cells could pick up by themselves. The outer hair cells ‘boost’ the signal, meaning we can hear sounds as quiet as a pin dropping.

Outer hair cells have special characteristics that allow them to work as amplifiers. One feature is ‘electromotility’ – they change shape in response to a change in voltage inside the cell, caused by a sound wave entering the cochlea and stimulating the cell. When stimulated by a sound wave, they contract (get shorter), and then, after the wave has passed, they relax and elongate.

So in essence, outer hair cells ‘dance’ in response to sound – you can see this in action on Professor Jonathan Ashmore’s lab webpage, where you can watch the video below of an outer hair cell ‘dancing’ to ‘Rock Around The Clock!’

As they contract and relax (which they can do many times each second), they push and pull on a structure in the cochlear called the basilar membrane, which is already vibrating because of the sound entering the ear. The outer hair cell movement amplifies the movement of this membrane and thereby ‘boosts’ the signal which is sent to the brain.

Above is a diagram of the ‘organ of Corti’, the structure inside the cochlea which houses the hair cells and is the basic organ of hearing. Inner and outer hair cells are labelled – the yellow cells are supporting cells, which give structural and chemical support to the hair cells. The basilar membrane (or ‘basilar fiber’) is shown at the bottom of the image.

Why outer hair cells are important for our hearing

Outer hair cells increase how sensitive the inner ear is to sound, meaning that at some frequencies (pitches) of sound, we can hear sounds over a range of 120 decibels (from a whisper to a jet engine). Without the amplification provided by the outer hair cells, this range would decrease substantially, and our ‘normal’ hearing thresholds would be significantly higher.

It is the outer hair cells that tend to be lost first when someone develops hearing loss. The inner hair cells may still be there, and still able to respond to sound, but the sounds have to be much louder for them to detect them.

Therefore, we need to know as much as we can about how outer hair cells form, and what’s needed to make sure they work correctly, if we are to be able to develop therapies to restore hearing.

An outer hair cell control gene

Ikzf2 provides the recipe for a protein called Helios, which is a ‘transcription factor’ – it controls the activity of other genes within a cell. The researchers we funded had already discovered that mice with a mutation in this gene developed early-onset, progressively worsening hearing loss over time. So we funded them to find out more about this gene, and how mutations in it might cause hearing loss.

The research team at Harwell first studied where and when the Helios protein is present in the cochlea. They found that it was specifically produced in developing outer hair cells, at the point when they begin to mature into functional outer hair cells. This suggested that Helios is a key gene for the development of working outer hair cells.

At the same time, the researchers in Maryland assessed the activity of genes across the whole inner ear, to learn more about outer hair cells and the genes that are needed for them to work correctly. They also flagged the Ikzf2 gene as being important, suggesting that Helios is required for the correct activity of many genes in outer hair cells.

With help from researchers at the University of Sheffield, the team looked more closely at how Ikzf2 is involved in outer hair cell function. What they found was that mutations in Ikzf2 significantly decreased the electromotility (or ‘dancing’) of the outer hair cells, meaning that they were unable to amplify sounds effectively. They linked this to another of their findings, that mutations in Ikzf2 caused two other key proteins involved in electromotility, to be present at much lower levels in outer hair cells.

Finally, the team studied what would happen if inner hair cells were engineered to produce Helios. They found that these inner hair cells showed reduced activity of inner hair cell-specific genes, and, more excitingly, that these cells started to display outer hair cell-like characteristics, with increased activity of outer hair cell genes, and they even started to dance!

What this means

This research, which was published in the prestigious research journal Nature, shows that Ikzf2/Helios is a crucial factor in ensuring that outer hair cells develop correctly, and can carry out all the functions they need to, so that we can hear. This is important because we now know that we will need to switch this gene on to correctly regenerate outer hair cells. This knowledge is therefore vitally important for the development of treatments to restore hearing, whether gene therapies, stem cell therapies or drug treatments.

Further information

This research was published earlier this year in the journal Nature – you can read the abstract on the PubMed database.

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Image credit: Madhero88 (CC BY-SA 3.0 – https://creativecommons.org/licences/by-sa/3.0), from Wikimedia Commons)