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Hair cell damage in the inner ear is becoming increasingly more common. More children, and adults, are exposing themselves to loud noises via concerts or headphones, and there are other various environmental factors as well. There are medicines and ototoxins, diseases, and overstimulization issues that also contribute to hair cell damage. Since this is becoming a more common issue, researchers are developing ways to regenerate the hair cells within the inner ear. This is necessary because the loss of hair cells can lead to hearing loss. Additionally, it can lead to problems with balance and the overall quality of life. While hair cell regeneration in humans is a possibility of the future, it will not be successful without further research and development.
The loss of hair cells in the inner ear leads to a sensorineural hearing loss. This type of loss usually occurs in the cochlea, which is within the inner ear and it is vital to processing sound as it is the primary organ of hearing (Cotanche, 2008). This type of loss is very difficult to treat as hair cells do not reproduce on their own, so once they are lost, the loss is permanent. Sensorineural hearing loss occurs due to hair cell loss, damage, hair cell degeneration, and other various sources (Izumikawa, Minoda, Kawamoto, Abrashkin, Swiderski, Dolan, et al. 2005).
To explain the difficulty in regenerating hair cells, it is best to cover some of the anatomy of how the cochlea works in the hearing process. This will provide a better understanding of treatment. Once sound enters the ear, it changes from acoustic to mechanical energy in the middle ear. From the middle ear, it is sent to the inner ear where it changes from mechanical to hydraulic energy. When the wave of energy reaches the cochlea, it changes back to mechanical energy, and then chemical energy within the hair cells. The transduction process is vital for hearing, as the brain cannot process acoustic energy. If the chemical process is absent or minimal, the brain cannot process the sound, and thus hearing will be impaired. (Hume, Oesterlie, Raible, Rubel, & Stone, 2010).
In cell development, there are sensory and nonsensory supporting cells (Ozeki, Oshima, Senn, Kurihara, & Kaga, 2007). They alternate in their development, with nonsensory supporting cells at the bottom holding the sensory hair cells into place. According to the lateral inhibition theory of cell development, the supporting cells replace the hair cells when they are damaged, and then more supporting cells are recreated as needed. The supporting cells divide without assistance to replace the missing cells. This is the ideal cure to hair cell regeneration and knowledge of how this process works is vital to researchers. With this information, it enables them to find a way to recreate this cell division process. In the bird’s organ of hearing, they are capable of this self repair. However, in humans it is still being assessed as merely a possibility. The problem is that this type of cell division does not happen spontaneously in the human organ of hearing. Researchers are still developing ways to make this event happen through the use of growth hormones, stem cells, genes, etc. (Walshe, et al. 2003)
As mentioned, human hair cells do not regenerate on their own, and this was because not all cells have the ability to divide (White, Doetzlhofer, Yun Shain, Groves, & Segil, 2006). One of the biggest challenges for researchers was getting cells to divide that normally do not possess this ability. Once the hair cells were damaged or lost, it resulted in hearing loss, or even the possibility of a cochlear implant to enable hearing. Again, hearing loss may cause balance issues as there are hair cells in the vestibular system. (Ozeki, et al. 2007)
Why are birds able to regenerate cells and humans cannot? Birds, however, had the ability to regenerate hair cells automatically, once they were lost or damaged. Researchers are currently still studying these animals to find out why they possess this ability. Thus far, they have discovered that birds were able to restore neural connections as a functional unit. This means that instead of having different cells, performing various functions and regenerating separately, in birds they regenerated as a whole. (Walshe, et al. 2003).
A more in-depth look at bird’s regenerative ability revealed that once a bird’s hair cell was lost or damaged, the auditory nerve retreated from the cell (Matsui & Ryals, 2005). Once the innervation was removed, the process of replacing the cell could begin. A signal came down from the Notch, notifying the bird’s organ of hearing to begin the replacement process (Stone & Rubel, 2000). Bird’s have a different organ of hearing than humans. The basilar papilla in a bird is similar to the cochlea in a human. It controls the hearing process and in their case, hair cell regeneration. (Hume, Oesterlie, Raible, Rubel, & Stone, 2010). Their hair cells then had the ability to proliferate, or to multiply excessively as needed to repair themselves. After the cells multiply, they transdifferated or replaced the dead cells, and then they were re-innervated by the auditory nerve. This is an amazing process that occurs automatically within birds. (Stone & Rubel, 2000)
When looking at possibilities for hair cell regeneration within humans, proliferation and transdifferation are two proposed options for repair and both are dependent upon each other. During the proliferation process, cells multipled rapidly in order to replace the damaged or dead cells. However, in the transdiffereration process, the proliferated cells were stimulated in an attempt to repair the damaged cell. Stimulation allowed the cell to divide, and while the new division replaced the supporting cell, the supporting cell took place of the damaged hair cell. One of the main concerns with this process was the restructuring of the cells. Would this change alter the organ of Corti in humans? If it does, what is the affect this would have on hearing? The only way this process will be effective is if the transdifferated cell replaces itself. What could happen if the cell does not replace itself? Would there be a bunching of supporting cells, or even possibly missing supporting cells? If supporting cells are missing, will there be a space and nothing to hold on to the newly generated hair cell? These are questions that researchers are still trying to answer before conducting experiments in humans, and most definitely before approving this type of resolution as valid for hair cell regeneration. (Mastui, et al. 2005).
To recreate the proliferation process in humans, genes must be present or injected as this does not happen naturally (Matsui, et al. 2005). Additionally, Kopke, Jackson, Geming, Rasmussen, Hoffer, & Frenz (2001) found that insulin can increase the cell response. Thus, if the cell does not proliferate after being exposed to the gene, insulin can be added to increase the likelihood that it will divide.
The primary gene involved in proliferation is Atoh1. Once injected into the organ of Corti, it can function as a non-expressing supporting cell, an expressing hair cell, or it can even be expressed but not function as a sensory cell (Ozeki, et al. 2007). Atoh1 regulates “common cellular precursor’s” in cell differentiation, which is why it is seen as the primary gene in hair cell regeneration. (Izumikawa, et al. 2005).
Matsui et al. (2005) used microarray to establish which gene was expressed and its location. This assessment was great for inner ear analysis given the specificity and intricate structures. Additionally, they were able to look at transcription factors to determine which genes played specific roles. Their results found that there were six-hundred factors in both the vestibular and auditory system, and only forty in one organ.
Another theory involved in hair cell regeneration or cell development, is the use of growth factors. They are associated with the differentiation and proliferation process, but suggest that instead of genes, these growth factors cause the regeneration (Kopke, et al. 2001). Matsui et al. (2001) suggests that macrophages, or white blood cells, are housed within tissue and they go to the dying cells. Once in the vicinity, they either repair or remove the dying cell. This process most frequently occurs after some type of trauma. A flaw with this theory was that the researchers were unclear of the current function of the macrophages within the inner ear of humans. Obviously, this process was not currently working spontaneously, as humans cannot regenerate cells without assistance. However, researchers would like to better understand this process within the inner ear to determine if hair cell regeneration is possible by the production of growth factors in general. (Oregon Health & Sciences University, 2008).
Other significant contributors to the process of proliferation are leukocytes-activators or “progenitor cell proliferation” (Stone & Rubel, 2000). There were three subtypes of progenitors that may play a role in this process. The first was the neuronal-colony-forming type which were the most similar to stem cells (Stone, Choi, Wooley, Yamashita, Rubel, 1999). The second and third type were the progency and mash1 which had very little proliferate ability. These variances in progenitor cells may explain the differences in regeneration. Furthermore, it may also explain why other animals can regenerate while humans cannot. Additional research needs to be conducted to determine the exact role these ‘activators’ play in the proliferation process. (Stone & Rubel, 2000).
The transdifferation process, in comparison to proliferation, is about as complex. In this process, the cells are transformed from supporting cells into hair cells (Ozeki, et al. 2007). This process can be initiated by the use of the gene Atoh1 as well as Retinoic acid (Kopke, et al. 2001) and (White, et al. 2006). One flaw in this process is that the hair cell may not always be functional after transformation (Kopke, et al. 2001). This is because the cell needs a brain-derived neurotrophic factor which is provides a neurological connection and lack of it can prevent function of the generated hair cell. Furthermore, it is important for vestibular ganglion neurons to survive, it protects neurons from ototoxins which may cause future damage to the cell, and when combined with insulin and retinoic it is known to cause vestibular function. Ideally, this means once we get control of how this process works, we could possibly treat some balance disorders. Given all of this information, it is important to note that neural elements are not needed for the regeneration process itself and it does not affect the production of hair cells; it is only necessary for function and innervations of the hair cell (Stone & Rubel, 2000).
Now that there is a better understanding of the anatomical process involved in the inner ear, it is best to assess the proposed treatments for human hair cell regeneration. The first treatment was the reconstruction of the organ of Corti. Ideally, Ozeki et al. (2007) found that doctors should inject progenitor cells into the inner ear. After the injections, the hope was that the cells would differentiate on their own into supporting or hair cells as necessary. This meant that the supporting cells would differentiate into hair cells, and more supporting cells would be created.
The second proposed treatment was stem cell transplant. This became a possibility because stem cells had many properties that were beneficial to humans. Additionally, they had very similar properties to supporting cells, could generate in large numbers, and could take the form of different types of cells (Matsui, et al. 2005). One drawback of this treatment was the uncertainty if the new cell would be functional. An additional avenue of this type of treatment was to find out if progenitor cells could act like stem cells (Stone & Rubel, 2000).
As researchers progress in finding a successful treatment for regenerating hair cells within the inner ear, there are still many questions to be answered about the process. For one, why do only our vestibular cells show the possibility of regeneration (Matsui, et al. 2005)? This is interesting because Matsui et al. (2005) found that hair cells regenerate spontaneously in the vestibule but not in the cochlea. Is it possible that vestibular cells do not need a replacement cell? Why is it that the auditory system cells do not regenerate (Rubel, 2005)? Do supporting cells lack a replacement cell; are there unknown gene functions; are signals being blocked that regulate cell regeneration (White, et al. 2006)? Until these questions are answered, significant research still needs to be conducted in this area of treatment.
The possibility that hair cell regeneration will someday lead to the restoration of hearing still exists. Many avenues have been addressed by various researchers ranging in everything from genes, growth factors, and stem cell replacement. However, if research reaches the point where hair cell regeneration is successful, this does not resolve the issue of whether hair cell regeneration alone can restore hearing in a hearing impaired individual. There is still the idea that not all regenerated cells will be functional and innervated, and the regeneration process may not provide full regeneration. Thus, the result will still be a hearing impairment. Unless hair cell regeneration can overcome all of these obstacles, the need for a cochlear implant may still be necessary.
1. Cotanche, D. (2008). Genetic and pharmacological intervention for treatment/prevention of hearing loss. Journal of Communication Disorders, 41(5): 421-43.
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