ReviewA brief history of hair cell regeneration research and speculations on the future
Highlights
► Discovery of hair cell regeneration was serendipitous. ► Not known or generally believed possible before 1986–87. ► The future is bright – “we've come a long way, baby”!.
Introduction
Damage and loss of hair cells in the inner ear through aging, exposure to noise, environmental chemical toxins, medications, disease and genetic disorders cause hearing and balance disorders in millions of people each year. In the past, clinicians seldom envisioned treatments of the inner ear to prevent hearing or balance disorders, or treatments to restore the cells that are damaged or lost. Instead, prevention of hearing loss is mainly limited to peripheral protection (e.g., ear plugs), and treatment is based on either increasing the stimulation of remaining hair cells (amplification) or bypassing the hair cells entirely (cochlear and brainstem implants). While enormous progress has been made during the past fifty years in those treatment modalities, we believe that during the next two-to-five decades, biologically-based methods will allow prevention of hearing and balance disorders and replacement of lost receptor elements through regeneration or transplantation. This prediction is based on two important discoveries that occurred over the past three decades. The first, with overwhelming importance to all of biology and medicine, is the discovery that most cell death is governed by the activation of a well-conserved and relatively small number of pathways that have been grouped together under the name of “apoptosis”. This important discovery forms the basis for research aimed at developing treatments that will prevent a significant percentage of hearing and balance disorders. The second discovery was mainly of interest to hearing biologists; the discovery that most vertebrates have the capacity to repair and restore function to the damaged inner ear through the regeneration of hair cells. Most of this contribution will review the history of this latter discovery, highlighting some of the most important findings of the early period of the field. In addition, we indicate where some of this germinal research is providing exciting prospects for today and for the future.
The potential for new hair cell production throughout life in some vertebrates has been recognized for over 80 years. For example, Leon Stone studied regeneration of lateral line amputation and regeneration of the entire tail in amphibian embryos in the 1930s (Stone, 1933, 1937). In the early 1980s, a number of groups showed continuous production of hair cells in the inner ear of mature rays and fishes (Corwin, 1981, 1983; Popper and Hoxter, 1984). These studies demonstrated that addition of hair cells to the periphery of vestibular epithelia in many cold-blooded vertebrates occurs throughout life, as the animals continually grow. Until the late 1980's, it was generally accepted that warm-blooded vertebrates could not form new hair cells after development, either normally or in response to damage. This assumption was not challenged for several reasons. First, it appears that earlier investigators had not attempted to examine the possibility that hair cells in the inner ear or lateral line organs of cold-blooded vertebrates would regenerate after localized damage to these organs. Furthermore, it was already known that little growth of inner ear sensory organs occurs in mammals or birds after they reach maturity, and that mammals show little recovery of hearing after hair cell damage (e.g., McGill and Schuknecht, 1976; Blakeslee et al., 1978; Li, 1992; Sliwinska-Kowalska et al., 1992). Finally, it was generally assumed that post-embryonic production of sensory or neuronal cells in mammals is limited to a few unique sites, such as the olfactory neuroepithelium and taste buds (e.g., Farbman, 1990) and that specialized undifferentiated precursor cells were limited to these sites. Therefore, few if any researchers had investigated the possibility of hair cell regeneration in vertebrates. In both birds and mammals, all hair cells in the hearing organ (the organ of Corti in mammals and the basilar papilla in birds) are produced during embryogenesis or shortly thereafter (Ruben, 1967; Cotanche and Sulik, 1984; Katayama and Corwin, 1989). Although some mitotic activities may continue after embryogenesis, the new cells apparently do not differentiate into hair cells (Oesterle and Rubel, 1993). However, as discussed in detail below, serendipitous findings in two laboratories led to the realization that birds at any age can make new hair cells in their basilar papillae when damage has occurred (Cotanche, 1987a; Cruz et al., 1987; Corwin and Cotanche, 1988; Ryals and Rubel, 1988). Further, the vestibular epithelia of birds and most other non-mammalian vertebrates normally renew their hair cells throughout life (Jørgensen and Mathiesen, 1988), and production of new vestibular hair cells increases after damage (Weisleder and Rubel, 1993). Hair cell replacement in auditory and vestibular epithelia following hair cell loss results in near-complete recovery of hearing and balance function (reviewed in Bermingham-McDonogh and Rubel, 2003 and discussed below). These discoveries initiated a search for methods to stimulate regeneration or replacement of lost hair cells in mammals – a search that, if fruitful, will revolutionize the treatment of sensorineural hearing loss and balance disorders during this century.
In this review, we discuss the origins of some of the major trends in this field, which has now reached its 25th year anniversary and is virtually embryonic in the time-line of science. This is largely meant to be a historical account and therefore deals primarily with the period up to 2000, attempting to provide a historical perspective for the work presented in the remainder of this issue. Due to space limitations, we are unable to include a discussion of many relevant papers. Readers are encouraged to read the following articles or chapters for more comprehensive reviews of the literature: Corwin and Warchol, 1991; Stone et al., 1998; Bermingham-McDonogh and Rubel, 2003; Stone and Cotanche, 2007; Oesterle and Stone, 2008.
While this research has yet to result in a new treatment for hearing loss or balance disorders, it has stimulated a field of scientific inquiry that has shed enormous light on the capacity of the inner ear for hair cell regeneration, and it has raised hopes that a biological treatment for the hearing impaired will be available in the near future.
Section snippets
Initial experiments: discovery of hair cell regeneration in birds
Two serendipitous and nearly simultaneous findings in the mid-1980's suggested that mature birds are able to restore the population of hair cells lost following exposure to ototoxic drugs or intense noise. In 1985 and 1986, Raul Cruz, Paul Lambert, and Edwin Rubel performed an experiment intended to examine the time-course of aminoglycoside-induced hair cell death to the chicken basilar papilla (Fig. 1; Cruz et al., 1987). A large group of neonatal chicks was injected daily with 50 mg/kg
The source of hair cell regeneration: supporting cells and repair
The early studies that suggested new hair cells arise from mitotically dividing supporting cells (Ryals and Rubel, 1988; Corwin and Cotanche, 1988) were soon followed up by studies that confirmed this assumption. Further evidence for supporting cells as the source of regenerated hair cells after damage came from experiments performed in the lateral line neuromasts of live salamanders. These organs, found in amphibians and fish, contain both hair cells and supporting cells that are analogous in
Recovery of synaptic contacts, organ structure, and ultrastructure
Other important early experiments defined additional features of hair cell regeneration in the avian inner ear. For example, researchers investigated the time-course of the regenerative response, the dynamics of nuclear migration and cell shape changes during regeneration, and the innervation of the restored sensory epithelium. Of particular interest was the demonstration, first made by Yehoash Raphael (1992), of a stereotyped pattern of nuclear migration of the hair cell precursors during
Functional recovery
While restoration of synaptic contacts, stereociliary structure, and sensory organ organization were being examined, several groups investigated whether hair cell regeneration resulted in restored auditory and vestibular function. Studies using evoked brainstem potentials (ABRs) in chickens were the first to test the recovery of hearing after hair cell destruction. McFadden and Saunders (1989) examined recovery of ABR thresholds after acoustic trauma. In this situation, recovery appeared very
What about hair cell regeneration in mature mammals?
Following the discovery of hair cell regeneration in the inner ear of birds, several investigators turned to rodents to investigate the possibility that this capability is present but greatly attenuated in the mammalian inner ear. They quickly established that supporting cells in the mature mammalian auditory sensory epithelium (organ of Corti) do not form new hair cells but instead maintain mitotic quiescence, even after hair cell damage (Roberson and Rubel, 1994; Sobkowicz et al., 1997). In
Approaches toward identifying key regulators of hair cell regeneration
Armed with the understanding that non-mammals mount a robust regenerative response to hair cell loss while mammals do not, it was clear early on that the focus needed to shift toward identifying molecular mechanisms that could robustly promote or inhibit supporting cells to form new hair cells in animals that DO regenerate hair cells (non-mammalian vertebrates) and those that do not mount a robust regenerative response (mammals). To address this problem, it was first necessary to develop
The future
Scientific efforts in numerous laboratories over the past 25 years have made major contributions to our understanding of hair cell regeneration as a mechanism for restoring hearing or balance function after injury in mature animals. They have demonstrated that most or all non-mammalian vertebrates readily regenerate hair cells after damage, and regenerated hair cells develop normal features, become innervated, and communicate effectively with the brain. Second, investigators showed that adult
Conclusion
In the early 1980s, it was impossible for most auditory scientists to imagine clinicians could someday repair the damaged cochlea by inducing the production of new sensory cells to transduce sound into electrical signals conveyed to the brain. Today, thanks to work pioneered in the 1980s and 1990s, laboratories around the world are eagerly seeking ways to use the recent findings of modern biology to protect and repair the inner ear. The momentum driving this research will only continue to grow
Acknowledgments
We are grateful to Elizabeth Oesterle for helpful comments on the manuscript, to Kevin Whitham and Rebecca Lewis for help with figures, and to Dr. Douglas Cotanche for providing Fig. 2 and helpful comments on the manuscript. We dedicate this article to Dr. Douglas Cotanche, co-discoverer of hair cell regeneration, friend, mentor and colleague who has unselfishly shared his enthusiasm, ideas and scientific acumen throughout our long association and continuing to the present.
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