ReviewLead roles for supporting actors: Critical functions of inner ear supporting cells
Highlights
► Supporting cells are vital to the development and function of hair cells and neurons. ► Supporting cells mediate hair cell survival, death, and regeneration. ► Supporting cells eliminate damaged or dying hair cells from the sensory epithelium. ► Many functions of supporting cells are similar to those reported for glial cells.
Introduction
Hearing loss affects nearly 4 million American children and 36 million adults (NIDCD, 2010; NIDCD, 2006). Aging, noise trauma, ototoxic drugs, and hereditary mutations are all causes of hearing loss (Li-Korotky, 2012; Seixas et al., 2012; Cheng et al., 2009; Friedman and Griffith, 2003), a condition that has limited treatments and no known cure. In addition, in the United States, balance disorders affect over 600,000 individuals and similarly have few treatment options (NIDCD, 2010). Many studies aimed at understanding the mechanisms underlying hearing loss and balance disorders have focused on mechanosensory hair cells, the sensory receptor cells of the auditory and vestibular systems (Phillips et al., 2008). Fewer studies have examined the biology and functions of the supporting cells that surround hair cells. This review will discuss the emerging evidence indicating that auditory and vestibular supporting cells serve many critical functions, some of which are similar to functions carried out by glial cells (astrocytes, microglia, Schwann cells and oligodendrocytes), suggesting that supporting cells may represent a type of specialized glia.
The mammalian cochlea contains several types of supporting cells, each with a distinct morphology and a specific anatomical location within the organ of Corti (reviewed in Raphael and Altschuler, 2003). Deiters' cells provide structural support for the outer hair cells, which are positioned atop and in direct contact with the Deiters' cell layer (reviewed in Raphael and Altschuler, 2003). Pillar cells form the tunnel of Corti, which lies between the inner and outer hair cells. Hensen's and Claudius cells both lie lateral to the outer hair cells in the outer sulcus. Supporting cells are less well-characterized than hair cells and in striving for better characterization, analogies have been drawn between supporting cells of the inner ear and those of other sensory systems, including the olfactory sustentacular cells and the retinal Müller glia (Rubel et al., 1991). Some similarities and significant differences between auditory supporting cells and these other sensory supporting cell types will be discussed in this review.
Emerging evidence suggests that auditory and vestibular supporting cells serve important functions as mediators of hair cell development, function, death and phagocytosis (Tritsch et al., 2007; Jagger and Forge, 2006; Bird et al., 2010; Lahne and Gale, 2008). Recent reports also indicate that supporting cells may mediate the survival and function of SGNs (Zilberstein et al., 2012). Many of these supporting cell functions are paralleled by glia in their relationship with neurons. Glial cells support neuronal function and survival in many ways. For example, both astrocytes and oligodendrocytes provide trophic support for neurons (Wilkins et al., 2003; Banker, 1980). Astrocytes support neuronal function and survival by clearing glutamate from neuronal synapses (Rothstein et al., 1996) and buffering potassium through a system of gap junctions (reviewed in Leis et al., 2005). Microglia play critical roles in the response to neuronal injury, engulfing apoptotic neurons in the central nervous system (reviewed in Napoli and Neumann, 2009). Following neuronal death in the fish retina, Müller glia serve as neural precursors for regenerated retinal neurons and photoreceptors (Bermingham-McDonogh and Reh, 2011). Many of these functions of glial cells are similar to those that have been described for auditory and vestibular supporting cells.
Section snippets
Development and survival of hair cells and spiral ganglion neurons
In the developing mammalian cochlea, the onset of neuronal activity results from coordinated signaling from hair cells, supporting cells, and SGNs. Cochlear hair cells are depolarized upon deflection of their stereocilia (Flock, 1965; Russell et al., 1986), which triggers the release of glutamate from inner hair cells (IHCs) (Kataoka and Ohmori, 1994). Glutamate binds to synaptic receptors on adjacent SGNs, resulting in the generation of action potentials and transmission of the afferent signal
Hair cell death and survival
Auditory hair cells are both very sensitive in terms of detecting sound and also highly susceptible to damage. The mechanisms that determine whether a hair cell under stress ultimately lives or dies are only beginning to be understood. Recent studies have revealed some of the molecular signals that are activated in supporting cells in response to hair cell damage, and these findings suggest that supporting cells may act as critical mediators of hair cell death (reviewed in Gale and Jagger, 2010
Hair cell regeneration
While the mature mammalian vestibular system exhibits a limited capacity for hair cell regeneration, spontaneous hair cell regeneration has not been reported in the mature organ of Corti (Li and Forge, 1997; Zheng et al., 1999; Yamasoba and Kondo, 2006; Warchol et al., 1993). However, non-mammalian vertebrates have the capacity for robust regeneration of lost hair cells. The first reports of hair cell regeneration in birds were published in the 1980's (Cotanche, 1987; Corwin and Cotanche, 1988;
Summary
Supporting cells play many important roles in the inner ear, and some of those functions are analogous to those of glia in the central nervous system. During development, supporting cells are thought to mediate spontaneous inward currents in hair cells and SGN firing of rapid action potentials, which may be essential to develop neural connections and refine the tonotopic map of the cochlea. Supporting cells provide critical trophic factors to SGNs and are responsible for clearing
Acknowledgments
The authors would like to thank Dr. Doris Wu, Dr. Matthew Kelley, Dr. Meghan Drummond, and Dr. Jonathan Bird for their helpful comments and suggestions on the manuscript. The authors are also grateful to Dr. Jonathan Gale for many thoughtful conversations about supporting cells as well as constructive notes on the development of the text and figures of this manuscript. This work was supported by the NIDCD Division of Intramural Research.
References (140)
- et al.
Evolutionary divergence of the reptilian and the mammalian brains: considerations on connectivity and development
Brain Res. Brain Res. Rev.
(2002) - et al.
An in vivo tracer study of noise-induced damage to the reticular lamina
Hear. Res.
(2003) - et al.
Regulated reprogramming in the regeneration of sensory receptor cells
Neuron
(2011) - et al.
Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’
Trends Biochem. Sci.
(2012) - et al.
Sensorineural hearing loss in patients with cystic fibrosis
Otolaryngol. Head Neck Surg.
(2009) Regeneration of hair cell stereociliary bundles in the chick cochlea following severe acoustic trauma
Hear. Res.
(1987)- et al.
Hair cell and supporting cell response to acoustic trauma in the chick cochlea
Hear. Res.
(1990) - et al.
Hair cell damage produced by acoustic trauma in the chick cochlea
Hear. Res.
(1987) - et al.
Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds
Dev. Biol.
(2009) - et al.
Neuronal degeneration of primary cochlear and vestibular innervations after local injection of sisomicin in the guinea pig
Hear. Res.
(1993)
Outer hair cell loss and supporting cell expansion following chronic gentamicin treatment
Hear. Res.
A mechanism for sensing noise damage in the inner ear
Curr. Biol.
Wnt signaling, lgr5, and stem cells in the intestine and skin
Am. J. Pathol.
Closure of supporting cell scar formations requires dynamic actin mechanisms
Hear. Res.
Expression of LHX3 and SOX2 during mouse inner ear development
Gene Expr. Pattern.
Fgf signaling regulates development and transdifferentiation of hair cells and supporting cells in the basilar papilla
Hear. Res.
Comparison of activated caspase detection methods in the gentamicin-treated chick cochlea
Hear. Res.
KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness
Cell
Morphological evidence for supporting cell to hair cell conversion in the mammalian utricular macula
Int. J. Dev. Neurosci.
Hair cell regeneration in the chicken cochlea following aminoglycoside toxicity
Hear. Res.
Stem/progenitor cells in the postnatal inner ear of the GFP-nestin transgenic mouse
Int. J. Dev. Neurosci.
Recovery of the basilar papilla following intense sound exposure in the chick
Hear. Res.
The effect of gentamicin-induced hair cell loss on the tight junctions of the reticular lamina
Hear. Res.
Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla
Brain Res.
Scar formation in the vestibular sensory epithelium after aminoglycoside toxicity
Hear. Res.
Microglial clearance function in health and disease
Neuroscience
Neuronal death induced by nanomolar amyloid beta is mediated by primary phagocytosis of neurons by microglia
J. Biol. Chem.
Scar formation after drug-induced cochlear insult
Hear. Res.
Structure and innervation of the cochlea
Brain Res. Bull.
Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways
Immunity
Neuregulin and erbB receptors play a critical role in neuronal migration
Neuron
Ongoing production of sensory cells in the vestibular epithelium of the chick
Hear. Res.
Hair cell recovery in mitotically blocked cultures of the bullfrog saccule
Proc. Natl. Acad. Sci. U.S.A.
Mitotic and nonmitotic hair cell regeneration in the bullfrog vestibular otolith organs
Ann. N. Y. Acad. Sci.
Regenerated hair cells can originate from supporting cell progeny: evidence from phototoxicity and laser ablation experiments in the lateral line system
J. Neurosci.
Trophic interactions between astroglial cells and hippocampal neurons in culture
Science
Regenerative medicine for the special senses: restoring the inputs
J. Neurosci.
Expression of Prox1 during mouse cochlear development
J. Comp. Neurol.
Macrophage and microglia-like cells in the avian inner ear
J. Comp. Neurol.
Cell cycle progression in gentamicin-damaged avian cochleas
J. Neurosci.
Supporting cells eliminate dying sensory hair cells to maintain epithelial integrity in the avian inner ear
J. Neurosci.
Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4
Nature
Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold
EMBO J.
Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds
J. Comp. Neurol.
Atoh1 expression defines activated progenitors and differentiating hair cells during avian hair cell regeneration
Dev. Dyn.
Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea
Proc. Natl. Acad. Sci. U.S.A.
Variations in shape-sensitive restriction points mirror differences in the regeneration capacities of avian and mammalian ears
PLoS One
Regeneration of sensory hair cells after acoustic trauma
Science
Light microscopic evidence of hair cell regeneration after gentamicin toxicity in chick cochlea
Arch. Otolaryngol. Head Neck Surg.
Cell death in the inner ear
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2021, Cell ReportsCitation Excerpt :The sensory epithelium is spatially divided into two regions: striolar (central) and extrastriolar (peripheral). In addition to their roles as structural, homeostatic, and phagocytic functions, supporting cells serve as hair cell precursors following injury (Corwin and Oberholtzer, 1997; Janesick and Heller, 2019; Monzack and Cunningham, 2013; Wan et al., 2013; Wang et al., 2015; Warchol, 2011). At the periphery of the mitotically quiescent sensory epithelium is the transitional epithelium, a scantily characterized group of non-sensory cells that continue to proliferate in the early postnatal period (Figure S1A) (Burns et al., 2015; Gnedeva et al., 2017).