Hearing loss is a disability that affects over one billion people worldwide, severely impacting wellbeing and quality of life by affecting an individual’s ability to communicate and socialise with others.
Professor Brandon Cox and colleagues at Southern Illinois University School of Medicine, USA, have concentrated their efforts into understanding the process, mechanisms, and genes involved in hair cell regeneration in mice.
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Read the original research: doi.org/10.3389/fncel.2022.841864
Image Source: Adobe Stock Images / Vladimir Voronin
Hello and welcome to Research Pod! Thank you for listening and joining us today.
In this episode we look at the work of Associate Professor Brandon Cox and colleagues at Southern Illinois University School of Medicine, USA, who have been studying the regeneration process of hair cells in new-born mice. Their recent findings give us a better understanding of this process in mammals, edging us closer to the goal of one day restoring hearing loss in humans.
Globally, hearing impairment is a common disability – especially among elderly adults. Hearing loss caused by damaged sensory receptor cells, or hair cells, inside the ear cannot be reversed – and regeneration of this type of cell does not occur in humans. Hearing loss is a disability that affects over one billion people worldwide. This condition can severely impact wellbeing and quality of life by affecting an individual’s ability to communicate and socialise with others. If not addressed, hearing loss can eventually lead to further health problems such as memory loss, social isolation, and mental health illness.
Current treatments for hearing loss include hearing aids and cochlear implants, but neither facilitate a return to unassisted hearing or recovery of the damaged ear tissue. Inspired by the ability of some animals to regenerate the hair cells needed for hearing, Professor Brandon Cox and colleagues at Southern Illinois University School of Medicine have concentrated their efforts into understanding the process, mechanisms, and genes involved in hair cell regeneration in mice. Through a number of publications, the team have shown that spontaneous regeneration of hair cells can occur in the first week after birth in mice, and more recently have mapped the source of such regenerated cells while describing their characteristics. This wealth of data has significantly contributed to improved understanding in the field of hearing loss.
The human ear consists of three parts: the outer ear, the middle ear, and the inner ear. All of these play a specialised role in transferring sound waves from the surrounding environment to the brain. Within the inner ear, sound waves are converted into electric signals that are conveyed to the brain to be interpreted as sounds. This conversion happens inside a snail-shaped structure called the cochlea.
The cochlea is lined by specialised cells called hair cells which carry sensors for detecting sound waves. Hair cells take their name from their hair-resembling projections, known as stereocilia bundles, which are also responsible for their soundsensing function. There are two types of hair cells: inner hair cells, which are responsible for converting sound vibrations into electrical signals that travel to brain, and outer hair cells, which amplify quiet sounds that enter the cochlea. Around the hair cells lie accessory cells – the cochlear supporting cells – which protect and provide structural support to the hair cells.
Damage to the hair cells results in permanent hearing loss because human hair cells cannot regenerate. However, in other organisms such as birds, fish, and new-born mice, hair cells do have the potential to regenerate – and hearing in both birds and fish is restored. The Cox laboratory has studied the process of hair cell regeneration using mouse models for a decade now. So far, the team has discovered a number of fascinating facts about the hair cell regeneration process itself. Their work provides valuable insight into the factors that control this process and affect the regenerated cell functionality and survival. Their work brings us closer to restoring hearing in humans whose hearing loss has occurred due to age; ototoxic drugs, that kill hair cells and cause hearing loss; or irreversible structural damage caused by loud noise.
Initial work by Cox and her fellow researchers published in the journal Development revealed spontaneous regeneration of mouse cochlear hair cells following injury, sparking interest that mammals also have the potential to regenerate these cells. This study laid the foundation for future studies to explore the role of supporting cells in this process and determine the underlying mechanisms.
To study the ability of new-born mouse hair cells to regenerate after damage, the researchers needed to kill the hair cells soon after birth. Because mice cannot hear until they are two weeks old, noise could not be used to destroy hair cells. Furthermore, the option of using ototoxic drugs was not possible due to their potential lethal effects in young mice. Instead, the researchers created two mouse models that allowed for selective killing of the hair cells by an injection.
Surprising results followed where the team discovered that after hair cells were killed, the neighbouring cochlear supporting cells spontaneously converted into hair cells but this only occurred within the first week of life, not later. These newly formed cells expressed many hair cell-specific proteins and had stereocilia bundles, although many of them died shortly after their formation. However, the experiments demonstrated the promising ability of neonatal cochlear supporting cells to regenerate hair cells after injury, offering the chance to study the regeneration process in a mammal – therefore a closer model for humans than birds or fish.
The exciting findings of their initial study raised even more questions. The regenerated hair cells had some of the qualities of typical hair cells, but could they further differentiate into functional inner and outer hair cells? As detailed in their recently published paper in the journal, Frontiers in Cellular Neuroscience, the Cox Lab focused on understanding the intricacies of the regeneration process including the supporting cell response to hair cell loss and the characteristics of the newly formed hair cells. They aimed to identify the new cells’ features using immunostaining techniques and known markers of the two hair cell types.
The Cox Lab researchers found that the supporting cells had an early response to hair cell damage by expressing a gene called Atoh1, which is necessary for making hair cells during development.
Although a large number of supporting cells responded to the injury by expressing Atoh1, only a small fraction of these cells matured to become a hair cell. Cox speculates that a certain amount of Atoh1 may be needed to stimulate supporting cell transformation or that other genes and factors central to the process are either missing or preventing the conversion process.
One of the most important findings in this study was that the majority of the regenerated hair cells are hybrids that expressed both inner and outer hair cell genes. Such genes included known markers of fully mature inner and outer hair cells namely, VGlut3 and prestin. In addition, the majority of regenerated cells were connected to nerves or neuronal fibres and had synapses – a special type of connection between cells that is necessary for the transfer of electrical signals to the brain. These findings have led the team to conclude that the factors which regulate the formation of inner and outer hair cells are no longer present after birth, leading to the inappropriate expression of proteins and eventually to an incomplete differentiation process and the formation of hybrid hair cells. Thus development of therapies to induce hair cell regeneration in humans would need to include factors that promote formation of the two hair cell types.
We now have a better understanding of the source of the regenerated hair cells, their characteristics, and limitations. But looking forward, can we induce the new hair cells to complete the maturation process and become functional? Can we stimulate even more supporting cells to convert into hair cells during the regeneration process in early life? Also, can regeneration in older mice be induced? Many questions still remain and further research is ongoing to answer these questions and shed light on why the hair cell regeneration process in mice is limited to the first week after birth. Studies could also help identify the factors and changes during the regeneration process that prevent the formation of fully functional, mature inner and outer hair cells.
The decade of work on this topic and the recent encouraging findings from the Cox Lab lead to a broader understanding of the regeneration process in young mice. Now, with additional funds secured from the Department of Defense, the team will use their tracing strategy to screen drug compounds with regenerative potential. Their work brings us a step closer towards the ultimate aim of discovering a way of restoring hearing in humans following permanent loss of hair cells.
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