The sensory epithelium of the mammalian cochlea comprises mechanosensory hair cells that are arranged into four ordered rows extending along the length of the cochlear spiral. The factors that regulate the alignment of these rows are unknown. Results presented here demonstrate that cellular patterning within the cochlea, including the formation of ordered rows of hair cells,arises through morphological remodeling that is consistent with the mediolateral component of convergent extension. Non-muscle myosin II is shown to be expressed in a pattern that is consistent with an active role in cellular remodeling within the cochlea, and genetic or pharmacological inhibition of myosin II results in defects in cellular patterning that are consistent with a disruption in convergence and extension. These results identify the first molecule, myosin II, which directly regulates cellular patterning and alignment within the cochlear sensory epithelium. Our results also provide insights into the cellular mechanisms that are required for the formation of highly ordered cellular patterns.

Hypothesis: Local application of recombinant human insulin-like growth factor 1 (rhIGF-1) via a biodegradable hydrogel after onset of noise-induced hearing loss (NIHL) can attenuate functional and histologic damage. Background: The biodegradable gelatin hydrogel makes a complex with drugs by static electric charges and releases drugs by degradation of gelatin polymers. We previously demonstrated the efficacy of local rhIGF-1 application via hydrogels before noise exposure for prevention of NIHL. Methods: First, we used an enzyme-linked immunosorbent assay to measure human IGF-1 concentrations in the cochlear fluid after placing a hydrogel containing rhIGF-1 onto the round window membrane of guinea pigs. Second, the functionality and the histology of guinea pig cochleae treated with local rhIGF-1 application at different concentrations after noise exposure were examined. Control animals were treated with a hydrogel immersed in physiologic saline alone. Results: The results revealed sustained delivery of rhIGF-1 into the cochlear fluid via the hydrogel. The measurement of auditory brainstem responses demonstrated that local rhIGF-1 treatment significantly reduced the threshold elevation from noise. Histologic analysis exhibited increased survival of outer hair cells by local rhIGF-1 application through the hydrogel. Conclusion: These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL.

In vertebrates, perception of sound, motion, and balance is mediated through mechanosensory hair cells located within the inner ear. In mammals, hair cells are only generated during a short period of embryonic development. As a result, loss of hair cells as a consequence of injury, disease, or genetic mutation, leads to permanent sensory deficits. At present, cochlear implantation is the only option for profound hearing loss. However, outcomes are still variable and even the best implant cannot provide the acuity of a biological ear. The recent emergence of stem cell technology has the potential to open new approaches for hair cell regeneration. The goal of this review is to summarize the current state of inner ear stem cell research from a viewpoint of its clinical application for inner ear disorders to illustrate how complementary studies have the potential to promote and refine stem cell therapies for inner ear diseases. The review initially discusses our current understanding of the genetic pathways that regulate hair cell formation from inner ear progenitors during normal development. Subsequent sections discuss the possible use of endogenous inner ear stem cells to induce repair as well as the initial studies aimed at transplanting stem cells into the ear.

The mammalian auditory sensory epithelium, the organ of Corti, is a highly ordered cellular structure that comprises two types of auditory hair cells and several types of nonsensory supporting cells. During embryogenesis, a stereotyped sequence of cellular and molecular events is required for its development. These processes are assumed to be regulated by multiple growth and transcription factors. However, the majority of these factors have not been identified. One potential regulator of cochlear development is the insulin-like growth factor (IGF) signaling family. To examine the roles of the IGF pathway in inner ear formation, cochleae fromIgf1rmutant mice were analyzed. Deletion ofIgf1rleads to several changes in inner ear development including a shortened cochlear duct, a decrease in the total number of cochlear hair cells, and defects in the formation of the semicircular canals. In addition, maturation of the cochlear sensory epithelium was delayed at the transition point between cellular proliferation and differentiation. To determine the molecular basis for these defects, inhibition of IGF signaling was replicated pharmacologicallyin vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well asAtoh1expression through the phosphatidylinositol 3-kinase/Akt signaling pathway. These results demonstrate novel roles for IGF signaling in inner ear development including regulation of vestibular formation, length of the cochlear duct, and the number of cochlear hair cells. The results also provide new insights regarding the pathological processes that underlie auditory defects in the absence of IGF signaling in both humans and mice.

Sensorineural hearing loss (SNHL) is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.