Tickle, Jacqueline A. BSc (Hons); Furness, David N. PhD
Ms. Tickle is a postgraduate researcher, and Dr. Furness is a reader at the Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom.
Stem cells, or other replacement cells, provide new options treating illnesses or disorders resulting from cell loss in the body. Stem cells have the capacity to turn into other types of cell and can be obtained from various sources, including the patient. We examine one potential way that stem cell replacement could prevent age-related hearing loss by preventing degeneration of certain cells of the cochlea.
The cochlea's ability to transduce acoustic energy, delivering signals perceived as sound, declines with age. Hearing frequency ranges for humans at birth is from 20 Hz to 20 kHz, and presbycusis occurs between 16 kHz to 18 kHz, progressing lower and resulting in speech difficulties and localizing sound in noisy environments.
Presbycusis is classified as a sensorineural hearing disorder and typically presents in those aged 50 to 60 years. (J Neurosci 2007;27:11172; Hear Res 2010;264[1-2]:98.) Approximately 77 percent of those aged 70 to 80 in the United States and 85 percent in the Europe are affected by presbycusis. (Eur Arch Otorhinolaryngol 2011;-268-:1101.) Reluctance to acknowledge the aging process and passive acceptance that hearing loss is an inevitable part of aging may mean the actual percentage to be higher. (Lancet 2005;366: 1111.) Presbycusis can be a combination of the aging process and other insults such as lifetime exposure to noise. Studies have shown, however, that it also occurs in animals that were not subjected to ear-damaging, ototoxic influences. (Lancet 2005;366:1111; Laryngoscope 1986;96:1391; Hear Res 2002;172[1-2]:172.) Studies of human temporal bones have also revealed different pathologies related to presbycusis. (Ann Otol Rhinol Laryngol 1993;102[1 Pt 2]:1.)
Sensorineural hearing loss is attributed to the loss of sensory hair cells and spiral ganglion neurons that transmit information from the cochlea along the auditory nerve, but also can be caused by the loss of spiral ganglion neurons independent of hair cell loss. (JAssoc Res Otolaryngol 2011;12:711.) Efforts to find a clinical solution to sensorineural hearing loss have led to attempts to replace hair cells or neurons in animal experiments by promoting regeneration or use of stem cells.
Regenerating stem cells to replace hair cells or neurons has been studied primarily in nonmammals because it occurs naturally in birds and fish. Gene manipulation is one way to stimulate cell regeneration in mammals. New hair cells were produced in an adult mouse when the gene for protein p27kip1, which helps inhibit cell division, was removed. (Proc Natl Acad Sci U S A 1999;96:4084.) Inserting a gene for the protein ATOH1, which is linked to hair cell development, was successful in adult deaf guinea pigs, and marked the first time cochlear hair cell regeneration was achieved in a mammal. (Nat Med 2005;11:271.) The new hair cells, however, were not positioned normally and lacked a mature appearance. Using stem cells to replace hair cells or spiral ganglion neurons is less advanced, although it is being investigated. (Drug Discov Today 2010;15[7-8]:283.)
A longitudinal study of 432 participants tried to define the pathology of age-related hearing loss using distortion product otoacoustic emissions (DPOAE), a physiological measure of hair cell function, combined with hearing threshold measurement. The threshold is the quietest sound level that an individual can hear, and is tested at different frequencies. Neural presbycusis is present if DPOAEs are normal but hearing thresholds are poor. In other words, the hair cells work normally, but the spiral ganglion does not transmit the signal well. A decline in DPOAEs, however, with a greater hearing threshold loss might suggest reduced endocochlear potential as in strial (metabolic) presbycusis. A greater decline in DPOAE versus hearing threshold would indicate absence of hair cells.
The findings showed a decrease in DPOAE with a greater decline in hearing threshold, suggesting that strial damage is the major pathology of an aging ear. (Hear Res 2002; 163[1-2]:53.) This and other studies suggest strial presbycusis is the most common cause of hearing loss in aging. (Lancet 2005;366:1111; Hear Res 2002;163[1-2]:53; Ear Hear 2006;27:91; J Neurosci 2002;22:9643.)
THE IMPORTANCE OF THE LATERAL WALL
Strial presbycusis is another common cause of hearing loss, and reflects degeneration in the stria vascularis and spiral ligament in the lateral wall of the cochlea. (Ann Otol Rhinol Laryngol 1993;102[1 Pt 2]:1.) Lateral wall pathology can cause a decrease in endocochlear potential, the physiological driving force that maintains a sensitive cochlea. Human studies into strial presbycusis are problematic because of the difficulty diagnosing endocochlear potential loss in the human ear. (J Assoc Res Otolaryngol 2010;11:419.)
The lateral wall in auditory function is significant because of potassium recycling, which generates endocochlear potential and maintains endolymph composition. (Figure 1.) This is based on homeostatic actions by cells of the spiral ligament called fibrocytes (Figure 2), in combination with the cells of the stria vascularis. Fibrocytes come in several shapes and sizes; they are typically divided into categories by their location and appearance. (Hear Res 2002;172[1-2]:172; J Assoc Res Otolaryngol 2011;12:437; Neuroscience 2009;162:1307; J Histochem Cytochem 2011;59:984.) The main ones are type I to type V, and seem to be primarily structural. Types II and V contain high levels of sodium and potassium involved in homeostasis; type III may be structural and involved in water regulation; and type IV is primarily structural with some role in potassium recycling. (Figure 2.)
THE ROLE OF FIBROCYTES
A number of studies have linked fibrocyte degeneration with the aging process. (Hear Res 2002;172[1-2]:172; J Assoc Res Otolaryngol 2011;12:437.) We believe, as a result of our work with mice, that the loss of fibrocytes may lead to other degenerative changes in the cochlea, including hair cell and spiral ganglion cell loss. (J Assoc Res Otolaryngol 2011;12:437.) A breakdown of potassium recycling may be the cause. Replacing fibrocytes or reversing their degeneration could prevent the progression of presbycusis in some forms of metabolic hearing loss.
Fibrocytes are mesenchymal — derived from the mesoderm in embryos — and are able to divide. Natural, ongoing production of fibrocytes in the cochlea can be seen, although this is not sufficient to prevent the presbycusis loss of these cells in CD1 mice. (J Assoc Res Otolaryngol 2003;4:164.) One approach to arresting or improving presbycusis is to stimulate the natural regenerative capacity; another would be to transplant fibrocytes. We have been developing cultures of fibrocytes for these approaches. (Figure 2.)
Cultures are somewhat easily grown from spiral ligament fragments and provide a model system to investigate proliferation, stimulate natural regeneration, or perhaps generate replacement cells. (Hear Res 1996;99[1-2]:71.) Cultured cells also can be genetically modified and engineered for specific functional purposes. Other researchers have attempted to inject mesenchymal stem cells from bone marrow into animals' inner ears, which in a clinical setting could be taken from the same patient to avoid rejection. This has not been done in models of presbycusis, but has been found to accelerate natural repair from ototoxic insult. (Neurobiol Dis 2011;41:552; Am J Pathol 2007;171:214.)
Could fibrocyte culture cells be transplanted? The accessibility of the cochlea's lateral wall compared with deeper internal structures makes it a possible therapeutic target. Most cell replacement or regeneration strategies are targeting the hair cells or neurons. Our approach is a potentially easier alternative, and our studies are aimed not just at growing fibrocytes but at developing a way to transplant them into the inner ear to prevent some forms of presbycusis.
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