HEAD & NECK SURGERY - Stanford University School of Medicine

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S TANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY R ESEARCH P ROGRAMS CURING HEARING LOSS AND UNLOCKING THE SECRETS OF HOW THE EAR WORKS Stefan Heller, PhD All hearing sensation is derived from the electrical output of a remarkably small number of sensory cells: fewer that 15,000 per inner ear at birth. These hair cells are the mechanoelectrical transducers of the inner ear: deflections of the sterociliary bundles on their apical surfaces lead to transmitter release from their basolateral poles, leading, in turn, to signal generation in the peripheral axons of the auditory nerve fibers. Most types of congenital and acquired hearing loss arise from damage to, or loss of, these sensory cells or their associated neurons. The incidence of heritable deafness is high: one child in a thousand is born deaf; another one in a thousand becomes deaf before adulthood. The prevalence of acquired hearing loss is rising, as the population ages, and as noise pollution steadily increases. It is estimated that one in three adults over the age of 65 has a handicapping hearing loss, and this impairment is largely due to the irreversible loss of sensory cells. Underlying the irreversibility of hearing loss in mammals is the incapacity to replace lost hair cells by cell division or by regeneration from endogenous cells 6 The image shows integration and differentiation of inner ear progenitor cells derived from mouse embryonic stem cells after injection into the chicken’s developing inner ear (otic vesicle). In (A), some of the injected cells, which are expressing the ß-Gal marker gene are found to integrate into the epithelium of the otic vesicle (arrow). Shown in (B) and (C) are embryonic stem cell-derived cells found 3 days after injection (in green). These cells start expressing markers of hair cells, such as myosin VIIA (red) and appear to have integrated well into the chicken auditory epithelium where they are surrounded by endogenous chicken hair cells (non green cells, labeled red). (D) and (E) show that the mouse cells, here visualized with a blue ß-Gal staining with developed hair bundles that are immunopositive for the hair bundle marker protein espin. in the inner ear epithelia. Hair cell replacement, either by stimulation of regeneration (as occurs naturally in nonmammalian vertebrates) or by transplantation of progenitor cells capable of differentiating into hair cells, remains therefore the ultimate goal in the development of treatment applications to reconstruct the damaged inner ear. Our recent work has focused on creating inner ear cell types, in particular hair cells and auditory neurons, from a renewable source. We have shown that embryonic stem (ES) cells and adult inner ear stem cells can serve as such a source, and we are currently exploring signaling pathways that control hair cell and neuronal (re-) generation in vitro and in vivo. Our research does not only focus on generating inner ear replacement parts. We are also exploring novel methods to deliver such replacement parts into the damaged cochlea or whether it is possible to use drugs to coax cells of the adult damaged cochlea into a prenatal status, which could result in self-repair of the damaged mammalian cochlea. In an independent line of research, we are pursuing the structural basis of hair cell mechanoreception. Although the individual molecular components of the mechanoelectrical transduction apparatus are not known, we and other laboratories have identified a number of potential candidates. Our goal is to solve the atomic structure of the different components of the transduction machinery to study the molecular hinges and mechanisms that mechanically gate the elusive ion channel that is central to our senses of hearing and balance. THE THERAPEUTIC RELEVANCE OF HAIR CELL BIOPHYSICS Anthony Ricci, PhD Hair cells are the sensory cells of the inner ear. They are responsible for converting mechanical signals into one recognized by the brain. Hair cells get their name from having a tuft of hair-like cilia at their apical surface. Deflection of these stereocilia opens mechanically-gated ion channels that convert the mechanical signal into an electrical signal. This process, termed mechanotransduction is critical to both hearing and balance. Perturbations of this system are associated with both temporary and permanent hearing loss, with age-related and noiseinduced hearing loss and may even be associated with tinnitus and vertigo. Understanding the mechanisms involved in regulating mechanotransduction may elucidate new and novel sites for intervention. Characterizing these pathways might also lead to new technological breakthroughs in hearing aid and cochlear implant development as well as in the design of novel noise prevention devices. Over the past several years my laboratory has identified several important attributes of mechanotransduction. First, we have discovered a new process, called fast adaptation that is critical for establishing frequency discrimination, or the ability of the ear to separate sound into its individual frequency components. Second, we demonstrated for the first time, biochemical regulation of mechanotransduction. This pathway may provide a new site for pharmacological intervention in preventing noise-induced hearing loss. Third, we have recently demonstrated the importance of mechanotransduction in controlling the electrical properties of hair cells. As mechanotransduction is very sensitive to its ionic environment, particularly the concentration of calcium, the importance of maintaining low levels of calcium bathing the hair bundle has become more apparent. Characterizing the regulation of extracellular calcium may provide a new pathway for intervention and may shed light on pathologies related to loss of ionic homeostasis within the ear. And finally we are involved in identifying a mechanism associated with mechanotransduction and the hair bundle that
may act to amplify low levels of sound and be a major contributor to determining how the ear can be sensitive to such low energy sound waves. Aside from converting a mechanical signal into an electrical signal, the hair cell must communicate with the brain through synaptic transmission. The hair cell-afferent nerve synapse is very sensitive to overstimulation where the nerve ending can swell and retract leading to hair cell loss. My laboratory has been investigating the functional properties of this synapse to identify the properties that make it unique in its ability to operate with such high fidelity and at such high rates. Here too, the goal is to identify pathways and mechanisms that might offer sites for intervention and modification. And finally, my laboratory is trying to determine whether hair cells require extrinsic factors, like innervation, mechanical stimulation or growth factors to mature into their final form. This is a critical question to answer in order to judge feasibility of therapies where hair cell regeneration from supporting cells or hair cell development from stem cells is being investigated as a new therapy to replace hair cells in damaged cochlea Isolated outer hair cell with sensory hair bundle (left). Upper right is patch electrode on hair cell body to measure electrical responses elicited by mechanically stimulating the sensory hair bundle (lower right). INNER EAR FLUORESCENCE MICROENDOSCOPY Nikolas Blevins, MD, Mark Schnitzer, PhD, Eunice Cheung, PhD We are developing a method to visualize functional hair cells and other cellular elements of the inner ear within the intact mammalian cochlea using fluorescence microendoscopy. Our laboratory has begun work on this minimally invasive in vivo imaging technique to provide high-resolution images of deep tissues previously inaccessible in live subjects. Using microendoscopes as small as 0.3 mm in diameter, we have successfully imaged individual red blood cells flowing within capillaries inside the mammalian cochlea. We are extending this work by labeling functional neural elements with fluorescent dyes to concurrently reveal mechanotransduction as well as microanatomy. Current work includes microendoscopy using a styryl dye (FM-143) in the guinea pig. It is anticipated that this will allow us View of live cochlear hair cells from a microendoscope to accurately map hair cell injury following ototoxin exposure, and to observe the recovery of hair cells from temporary threshold shift noise damage. The use of microendoscopes should provide an opportunity to observe specific hair cell populations over time – information previously unavailable through conventional techniques. An imaging technology to observe functional hair cells and dendrites within live MIcroendoscope Fall 2006 mammalian subjects will provide considerable benefit, and enable progress in a broad range of previously intractable hearing science questions. The success of inner ear microendoscopy will provide a basis on which inner ear surgery can be established. The inner ear is one of the last areas of the human body to remain largely inaccessible to direct examina- tion and surgical intervention. This is because of the combination of its small size and its extraordinary fragility to mechanical manipulation. The development of non-destructive imaging techniques will enable diagnostic and therapeutic manipulations, including the optimal placement of cochlear implant arrays, or the specific delivery of stem cells or growth factors to enable hearing restoration. 7
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HEAD & NECK SURGERY - Stanford University School of Medicine

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