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| This image illustrates a small region of the cochlea, including hair cells and supporting cells. At the top of each hair cell is a specialized structure called a stereociliary bundle. In the image, ea |
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| This image shows a cross-section through the cochlea of a mouse. Different kinds of cells are illustrated in different colors. Mechanosensory hair cells are blue and supporting cells are either green |
Hearing loss can occur in people of all ages, from newborns to the elderly. While the initial causes of hearing loss can be diverse, including viral infections, genetic mutations and long-term exposure to loud noise, in most cases, what ultimately occurs is damage to or death of the cells located within the cochlea, the snail shaped portion of the inner ear, resulting in hearing loss.
Inside the cochlea are four or five rows of specialized cells referred to as mechanosensory hair cells. These cells change the sound waves that enter the cochlea into small bursts of electricity, or signals. These electrical signals are carried into the brain through a specific type of nerve cell spiral ganglion neurons. In addition to hair cells, the cochlea also contains rows of cells that support and surround the hair cells. While these cells do not play a role in the detection of sound, their presence and normal function is required for hair cell survival. Hence their name: supporting ever, in some forms of inherited deafness (i.e., deafness caused as a result of an abnormal change in a gene), the supporting cells are initially affected. But since hair cells cannot survive without functioning supporting cells, the result is the same they also die and hearing loss results.
For reasons that are not understood, once humans lose their hair cells, they do not grow back, like skin cells do. However, when the spiral ganglion neurons are not damaged, as is often the case, the hearing loss may be partially restored with hearing aids that increase the activation of the remaining hair cells, or with a cochlear implant, a device that replaces the hair cells entirely.
While both hearing aids and cochlear implants often provide good recovery of hearing function, the development of a biological method to induce the production, or regeneration, of new hair cells has the potential to completely restore normal hearing without any type of prosthesis.
It is a mystery why humans, or any other mammals for that matter, cannot regenerate their hair cells. Studies in other animals, including birds, fi sh and reptiles, have demonstrated that they can regenerate their hair cells over and over again. The same studies have also shown that these regenerated hair cells develop from surrounding supporting cells. In contrast, in mammals, hair cells are only formed during a brief period in prenatal development. Because of this observation, several researchers have examined mammalian embryos to try to find the genes that are turned on in cells as they are forming into hair cells. In particular, researchers have searched for specific kinds of genes, referred to as transcription factors, because these genes turn on (express) other genes. Several years ago, a gene called Atonal Homolog 1 (Atoh1) was found to be turned on (expressed) in developing hair cells. When the Atoh1 gene was specifically removed from a developing mouse, no hair cells formed in the mouse's cochlea. By contrast, if cells within an embryonic mouse cochlea were forced to express Atoh1, then those cells would develop as hair cells even if they would normally have developed as supporting cells. Moreover, studies of certain species of birds indicated that the avian version of Atoh1 is turned on during hair cell regeneration. Together, all of these results suggested that if Atoh1 could be turned on in cells within an adult mammalian ear, then this might force those cells to develop as new hair cells.
The first step toward testing this idea was taken when a combination of drugs was used to deafen adult guinea pigs by killing most of the hair cells in their cochleae. Following this treatment, the Atoh1 gene was expressed in one cochlea of each animal using a type of therapy in which a specially-designed virus transports the gene to where it needs to go to be effective. After two months of recovery, the hearing of these animals was tested. Many of the animals actually showed some restoration of hearing function in the cochlea that had received the Atoh1 gene therapy. Moreover, an examination of the cochleae of these animals revealed cells that looked similar to immature hair cells.
In a similar series of experiments, hair cells located in regions of the inner ear that regulate balance were destroyed and gene therapy was again used to introduce Atoh1 into the remaining supporting cells. As was observed in the cochlea, some of these animals demonstrated a partial recovery in balance function. While these results are exciting, important follow-up experiments still must be done before it can be concluded that expression of Atoh1 is all that is required to make a new hair cell in an adult ear. In addition, independent confi rmation of the results from other laboratories, a crucial step for any experimental result, has not yet been reported. While progress is being made, the use of this type of gene therapy in a clinical setting remains highly experimental. These results are encouraging and supportive of the idea that expression of Atoh1 may have the ability to initiate growth of new hair cells. Nevertheless, we are a long way from the development and application of an Atoh1 gene therapy-based treatment for hearing loss in humans.
Unlike those of birds, fi sh and reptiles, the supporting cells within the cochleae of adult mammals appear to have lost the ability to change into different types of cells. However, studies have shown that the supporting cells in the cochleae of prenatal mice can change into hair cells under certain circumstances. This suggests that an unknown aspect of the aging process causes supporting cells to lose their transformative ability. Whereas gene therapy to force the cells to change into a different cell type is a possibility, another option might be to introduce entirely new cells that behave like young cells that still have the ability to develop into different types of cells. Cells with these abilities are referred to as stem cells. The stem cells that play a role in the early development of an organism embryonic stem cells are perhaps the best known types of stem cells but many other stem cell types also exist, including bone marrow and nervous system stem cells. In fact, a study published a few years ago even identified a small number of inner ear stem cells in the ears of adult mice. In addition, researchers are close to being able to make stem cells from skin cells, meaning that it might be possible to make stem cells for any person who needs them.
Regardless of where the stem cells come from, one approach to restore hearing might be to surgically place stem cells within the cochlea in such a way that they would fuse with the remaining cochlear structures and develop and function as hair cells. Depending on the type of stem cell, it might be necessary to treat the stem cells chemically and/or biologically to increase the likelihood of these cells becoming hair cells once placed in the ear. Ongoing research suggests that it is possible to increase the probability that a stem cell will become a hair cell, and in some cases cells that look very much like hair cells have been produced in the laboratory.
But, as is the case for gene therapy, a number of challenges remain with a stem cell strategy to hearing restoration. For reasons that are not completely understood, even when stem cells have been delivered to the correct part of the ear, most of them have failed to incorporate into the cochlea. Moreover, in addition to the many types of potentially useful cells that stem cells can turn into, stem cells can also form tumors. So, while improving the techniques for introducing stem cells into the cochlea is an important requirement, it will also be imperative to ensure that these cells can be safely introduced with no risk of causing cancer.
The criteria for biological hearing restoration treatments have changed considerably in the last 10 years. Prior to the development of the cochlear implant, the restoration of any hearing through biological methods would have been considered a success. But, when we consider how well cochlear implants work for most of the people who receive them, the criteria must be adjusted such that a biologically-based therapy for hearing restoration meets or exceeds the benefits that can be expected from a cochlear implant. This will probably require the ability to regenerate a much more complete cochlea, including specific types of hair cells as well as adequate supporting cells. It is possible that the use of gene therapy to introduce a single gene, like Atoh1, might be sufficient to restart the entire process of cochlear development, leading to regeneration of a normal cochlea, but it is also possible that we will need more direct control of multiple aspects of the regenerative process in order to regenerate a cochlea that can provide an understanding of speech and an appreciation of music.
The new discoveries described above illustrate how biomedical researchers are rapidly developing a much more complete understanding of the genetic and cellular processes that will need to be manipulated to initiate a biologically-based treatment for restoring hearing loss. Hopefully, ongoing research will continue to identify specific genes that regulate key aspects of hair cell and supporting cell formation. At the same time, research with stem cells offers the potential to be able to introduce a completely new set of young hair cells into a damaged or elderly ear. While we are still several years from a biologically-based treatment for hearing loss, this is an exciting time for hearing research and the potential for major breakthroughs has never been greater.
Matthew W. Kelley, Ph.D., is chief of the Developmental Neuroscience Section of the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, in Bethesda, MD.
