Of all the cochlear structures and cell types, the sensory hair cells, fewer than 15,000 at birth, are the Achilles’ heel of the auditory system. Loss of hair cells accounts for most hearing loss, affecting substantial proportions of the population (see Box 1
). Generally, outer hair cells (OHCs) are more sensitive than inner hair cells (IHCs) to insults that damage hearing and to the effects of aging1
. OHC loss, usually starting at the high-frequency basal region of the cochlea, leads to a substantial auditory threshold shift. More severe forms of hearing impairment generally involve the loss of IHCs. After hair cell loss, the organ of Corti undergoes gradual cytomorphological dedifferentiation of supporting cells; this is sometimes followed by a collapse of the tunnel of Corti, resulting in a structure that often features an unorganized mound of inconspicuous cells2–4
Box 1. Hearing loss and deafness in the United States and United Kingdom
- Men are more likely to experience hearing loss than women.
- About 2 to 3 children out of every 1,000 children are born deaf or hard of hearing.
- Approximately 36 million American adults (17%) report some degree of hearing loss.
- Approximately 26 million Americans (15%) between the ages of 20 and 69 have high-frequency hearing loss due to loud sounds or noise at work or in leisure activities.
- About 4,000 new cases of sudden deafness occur each year.
- Only 1 out of 5 people who could benefit from a hearing aid actually wears one.
- About 23,000 adults and 15,000 children have received cochlear implants.
Source: National Institute on Deafness and Other Communication Disorders, National Institutes of Health (http://www.nidcd.nih.gov/
- There are more than 34,000 deaf children in the UK.
- Approximately 840 children are born every year with moderate to profound deafness.
- About 1 in every 1,000 children is deaf at 3 years of age. This rises to 2 per 1,000 children aged 9 to 16.
- There are approximately 9 million deaf and hard-of-hearing people in the UK, of which about 698,000 are severely or profoundly deaf.
- About 3.5 million people of working age (16–65 years) are deaf or hard of hearing.
- About 55% of people over the age of 60 are deaf or hard of hearing.
- Approximately 2 million people have hearing aids, but only 1.4 million use them regularly.
- There are approximately 4 million people who could benefit from hearing aids but do not have them.
Box 2. Anatomy and physiology of the cochlea
Of all sensory hair cell–bearing organs, the mammalian cochlea, which converts sound waves into neural signals, is probably the most specialized and most complex. The organ of Corti within the cochlea () harbors a single row of approximately 3,500 inner hair cells (IHCs), the primary auditory transducers responsible for conversion of sound into neural signals. The IHC row is separated from the three rows of outer hair cells (OHCs) by highly specialized pillar cells that enclose the tunnel of Corti, which delineates a mechanical hinge whose movement is important for proper stimulation of the IHC stereocilia. The OHCs are situated on top of phalangeal supporting cells called Deiters cells. Other, morphologically distinct supporting cell types embrace the hair cell-bearing part of the organ of Corti. The OHCs play a key role in the frequency-specific amplification of basilar membrane motion; they connect with their stereociliary bundles to the tectorial membrane, an acellular structure that covers the organ of Corti along its entire length.
When sound travels through the middle ear, it is transmitted to the base of the cochlea via the stapes, which causes displacement of perilymph in the scala vestibuli, leading to movement of the basilar membrane (). This displacement results in a traveling wave that moves from base to apex and reaches a maximum at a specific place along the basilar membrane corresponding to the frequency of the stimulus46
. High frequencies—up to 20,000 Hz in humans—are represented at the cochlear base, and low frequencies—down to 20 Hz in humans—correspond to apical locations. This spatial arrangement of frequency representation and detection is called tonotopy. The sharp frequency tuning at a specific basilar membrane location is governed by the properties of an active system, the cochlear amplifier, that is attributed to OHCs. Nevertheless, frequency tuning also depends on other components, such as extracellular, cellular and molecular structures. Examples of these are the tonotopic changes of mass, composition and stiffness of the tectorial membrane47,48
; differences in hair cell morphology, such as cell and stereociliary length and compliance49
; and physiological differences, such as the changing conductances of the mechanoelectrical transduction channels along the tonotopic axis, which has been observed in nonmammalian cochleae50
Figure 1 Conceptual drawings of the normal, damaged and repaired organ of Corti. (a) In the normal organ of Corti, movements of the basilar membrane are relayed by means of hinging near the tunnel of Corti and shearing motions between outer hair cells (OHCs) and (more ...)
Regeneration of cochlear hair cells is considered the ultimate remedy for hearing loss. Nevertheless, what would seem to be a simple replacement of a single cell type turns out to be a remarkably complex endeavor when one takes into account the very different functions of IHCs and OHCs, as well as their precise integration into accessory structures, such as the tectorial membrane, and the restoration of organ of Corti micromechanics. This situation is aggravated by the morphological dedifferentiation of the cellular components of the organ of Corti, particularly in cases of progressive hearing loss. Consequently, hair cell replacement cannot be viewed as simply seeding new hair cells and getting them connected to the afferent auditory nerve. For proper restoration, hair cell regeneration needs to be conducted in the context of extensive cochlear restoration, either back to the original morphological configuration or into an alternative design featuring sensitivity and tonotopy, combined with longevity of the newly introduced cells ().
We divide this perspective into two parts: in the first part, we discuss current basic research in inner ear cell regeneration, as well as the unraveling of key genes involved in cochlear development and cell proliferation control. In the second part, we focus on therapeutic approaches and roadblocks, including delivery of cells, genes and small compounds.