Hair cell research - a cure for deafness?
13 June 2008
Professor Andy Forge of University College London explains the importance of hair cell research and the latest developments.
Why are hair cells important?
Hair cells are the sound receptors in the hearing organ, the cochlea. Death of cochlear hair cells is the primary cause of sensorineural deafness. Hair cells die as we grow older. They can also be killed by exposure to loud noise, and by ototoxic agents (chemicals, including some valuable therapeutic drugs, which can damage the ear). Once lost, cochlear hair cells in humans are not replaced, so the hearing impairment is permanent. Similar hair cells in the vestibular (balance) organ, also located in the inner ear, play a key role in detecting head movements. When these cells are damaged, the resultant loss of balance control can contribute to severe motility problems. Loss of vestibular hair cells is the major underlying cause of falls in the elderly population.
Hair cell regeneration
In non-mammalian vertebrates, most notably in birds, lost hair cells are replaced by new ones, resulting in almost complete cellular and functional recovery.
In birds, loss of hair cells provokes the supporting cells that surround each one to restart cell division. New hair cells and supporting cells arise from the daughter cells of those divisions. An alternative mode of hair cell regeneration is now also recognized. Some supporting cells can directly change (convert) into hair cells. This is thought to provide a “rapid response” to replace lost hair cells, but it needs to be complemented by division of supporting cells to enable complete recovery of the hair cell and supporting cell populations. Supporting cell conversion occurs in bird and amphibians such as the newt, but it has also been found to occur in the vestibular sensory tissues of mammals, providing a limited degree of hair cell regeneration.
However, there is no evidence of supporting cell conversion in the hearing organ of mammals and supporting cell division is not stimulated in either the cochlea or vestibular system in mammals. Some of the genetic factors that normally act to switch off cell division in the inner ear in mammals have been identified. Manipulation of these can lead to the production of extra hair cells during embryonic development and to continued cell division in the mature inner ear, when it is normally switched off. While this could suggest one possible approach to producing new hair cells when the original ones are lost, understanding how to manipulate the factors that normally regulate cell division represents a considerable scientific challenge. Not only must cell division be switched on when required but most importantly it must be switched off when the right number of cells has been made. Studies of regulation of the cell cycle, however, provide a tool with which to investigate how hair cells are formed.
Nevertheless, we are identifying ways to stimulate supporting cells to divide and then differentiate as (turn into) hair cells by attempting to identify the signalling pathways that act in birds and newts to stimulate hair cell regeneration. This will help to identify the barriers to hair cell regeneration in mammals that need to be overcome. Birds, like mammals, are warm blooded and because hair cell regeneration occurs so readily and extensively they are the major model for investigation of the bases of hair cell regeneration. Newts are important because they have an amazing capacity to regenerate a variety of body parts including tissues of the eye and are therefore an excellent model for assessing mechanisms of tissue regeneration. In collaboration with colleagues in the US who are examining regeneration of lens in the eyes of newts, we have identified one molecular regulator that may influence the capacity to regenerate both the lens and hair cells. We have also identified a protein that may be involved in regulating supporting cell division following hair cell loss in birds. In addition we have developed techniques for isolating the supporting cells from the newt inner ear that have shown it is possible to induce these cells to change into other types of cell including nerve cells. Subsequent work has shown a similar, and surprising, capacity to change in supporting cells isolated from the inner ears of mammals, including, most notably those of humans.
Using 'gene therapy' to create hair cells
We now have a greater understanding of how hair cells are initially generated during the development of the human embryo. Certain genes have been identified which can trigger precursor cells (cells from which other cells are formed) to differentiate as hair cells.
There is now some evidence that following loss of hair cells, introducing these genes into supporting cells can induce them to convert into hair cells. This provides a potential for 'gene therapy' to replace lost hair cells. Experiments have provided a “proof of principle” that the introduction of the appropriate genes into supporting cells in the mature organ of Corti (the sensory tissue of the cochlea) following loss of the original hair cell population, leads to the production of replacement hair cells. Similar procedures can produce replacement hair cells in the vestibular organs, leading to some degree of functional recovery after the “gene therapy”. We are now initiating studies to determine whether gene transfer can be applied to induce hair cell production in the vestibular sensory tissues from humans.
Transplanting stem cells into the cochlea
Stem cells are cells which are able to divide, and are therefore able to renew themselves. They are also able to differentiate into various types of specialised cell. Researchers have found that there is a very small population of stem cells in the mature vestibular (balance) organs of the inner ear in mammals and have discovered ways to “coax” these stem cells to differentiate as hair cells in a dish. A small population of stem cells also persists in the immature organ of Corti. Embryonic stem cells from mice have also been guided to differentiate as hair cell precursors. These cells have differentiated as hair cells when introduced into the developing sensory tissues of the inner ear, that is when put into an environment in which the normal hair cells are being formed. This opens the way for investigating the possibility of transplanting stem cells into the cochlea, where they could differentiate as hair cells.
Maintaining the environment for replacement hair cells
An important corollary of investigation of regeneration, by whatever mechanism, is to understand the environment into which the new hair cells will be placed. The tissue that remains after the hair cells are lost must be capable of sustaining the differentiation, survival and functionality of the replacement hair cells. To this end we are investigating the recovery processes in the cochlea after hair cells have been lost to identify the nature and characteristics of the repaired tissue that lacks hair cells. In parallel we are examining the ways in which the normal environment of the cochlea is maintained and how this is affected when hair cells die. This work should also provide information on which cell replacement procedure might be most effective and whether deafness caused by different agents is likely to respond to those replacement therapies.
Prevention is better than cure
It is obviously better to try to prevent death of hair cells than to find means to replace them when lost. We are beginning to understand the underlying biochemical pathways that are triggered by ototoxic agents, noise and by ageing which lead to death of hair cells. With understanding of these “cell death” pathways comes identification of means to intervene to rescue hair cells from death that would otherwise have occurred. A number of agents and procedures have now been identified that appear to protect hair cells from lethal damage. Some of these are entering clinical trials to determine whether indeed they are effective in preventing hearing loss. Such work holds out the prospect of new pharmaceutical strategies that will reduce the future incidence of hearing loss, and which may slow or prevent the progression of a hearing loss once initiated.
Conclusion
This new wave of research into hair cell regeneration is very welcome, and demonstrates that the excitement expressed in the mid-1990s about this area of research was not misplaced. However, it also demonstrates how complex and time-consuming such research is. Medical treatments for deafness and other hearing conditions are probably still some way off, but the funding we receive from organisations like Deafness Research UK is enabling us to continue developing our research strategies, and to make the discoveries which will pave the way for real treatment breakthroughs.
