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ABSTRACT: 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.
Trends in Amplification 04/2012; 16(1):4-18.
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ABSTRACT: 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 from Igf1r mutant mice were analyzed. Deletion of Igf1r leads 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 pharmacologically in vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well as Atoh1 expression 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.
Journal of Neuroscience 12/2011; 31(49):18104-18. · 7.11 Impact Factor
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ABSTRACT: Bone marrow-derived cells (BMDCs) are constitutively present in the vestibular end organs and in the endolymphatic sac, and may play a role in the maintenance of inner ear homeostasis.
The aim was to examine the distribution and characteristics of BMDCs in the vestibular end organs and in the endolymphatic sac.
Bone marrow-chimeric mice were generated by bone marrow transplantation from mice genetically labeled with enhanced green fluorescent protein to C57 Bl/6 mice to visualize BMDCs. Three months after bone marrow transplantation, inner ear specimens were processed for histochemical analyses.
BMDCs were widely distributed in the vestibular end organs and the endolymphatic sac, whereas there were differences in the phenotype and the distribution between the vestibular end organs and the endolymphatic sac. A subpopulation of BMDCs in the vestibular end organs expressed antigen-presenting protein MHC class II. Moreover, the density of BMDCs in the vestibular end organs increased in response to local mechanical stress.
Acta oto-laryngologica. Supplementum 11/2010;
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ABSTRACT: 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.
Development 06/2009; 136(12):1977-86. · 6.60 Impact Factor
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ABSTRACT: Previous studies have demonstrated the potential of cell transplantation for regeneration of spiral ganglion neurons (SGNs). However, the effect of surgical invasion on host cochleae has yet to be evaluated. The present study investigated the efficiency and invasiveness of our surgical procedure using a fine glass pipette for injections into the cochlear modiolus.
We examined the survival of transplanted embryonic stem cell-derived neurons in the cochlear modiolus of guinea pigs. Surgical invasiveness was assessed by measurements of electrically evoked auditory brainstem responses (eABRs) and SGN densities after an injection of 5 microl of saline into the cochlear modiolus.
All of the transplanted animals exhibited localization of transplanted cells in the cochlear modiolus. No significant alterations in the eABR thresholds or SGN densities were found following surgery.
These findings indicate that our procedure is a viable method for testing the potential of transplants for SGN replacement.
ORL 11/2008; 71(1):32-9. · 0.91 Impact Factor
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ABSTRACT: Immune-mediated inner ear disorder has been well established as a clinical entity; however, the innate immune system of the inner ear is a poorly understood area of research with high clinical and immunological importance. Although the presence of resident tissue macrophages in the inner ear has been suggested, there has been some controversy. In this study, we analyzed the origin of cochlear resident macrophages and the contribution of hematopoietic bone marrow (BM) to the recruitment of macrophages in the cochlea. To visualize the localization of BM-derived cells, BM chimeric mice were made by transplantation of hematopoietic stem cells, which were genetically labeled with enhanced green fluorescent protein, into lethally irradiated C57BL/6 mice. The distribution and characteristics of BM-derived cells in the mouse cochlea were studied immunohistochemically. We successfully identified the constitutive presence of tissue resident macrophages in the spiral ligament and spiral ganglion that are derived from BM in larger numbers than previously reported. Moreover, cochlear resident macrophages gradually turn over for several months during steady-state replacement by BM-derived cells, and the number of cochlear macrophages immediately increased in response to local surgical stress. The present findings demonstrate the hematopoietic origin of cochlear resident and infiltrating macrophages. Our study provides a novel anatomical and immunological basis for the inner ear and indicates that the cochlear resident macrophages would be a therapeutic target in inner ear disorders.
Journal of Neuroscience Research 07/2008; 86(8):1758-67. · 2.74 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL.
Ontology & Neurotology 11/2007; 28(7):976-81. · 1.90 Impact Factor
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ABSTRACT: Sensorineural hearing loss is a common disability, but treatment options are currently limited to cochlear implants and hearing aids. Studies are therefore being conducted to provide alternative means of biological therapy, including gene therapy. Safe and effective methods of gene delivery to the cochlea need to be developed to facilitate the clinical application of these therapeutic treatments for hearing loss. In this study, we examined the potential of cell-gene therapy with nonviral vectors for delivery of therapeutic molecules into the cochlea. NIH3T3 cells were transfected with the brain-derived neurotrophic factor (Bdnf) gene using lipofection and then transplanted into the mouse inner ear. Immunohistochemistry and Western blotting demonstrated the survival of grafted cells in the cochlea for up to 4 weeks after transplantation. No significant hearing loss was induced by the transplantation procedure. A Bdnf-specific enzyme-linked immunosorbent assay revealed a significant increase in Bdnf production in the inner ear following transplantation of engineered cells. These findings indicate that cell-gene delivery with nonviral vectors may be applicable for the local, sustained delivery of therapeutic molecules into the cochlea.
Molecular Therapy 01/2007; 14(6):866-71. · 6.87 Impact Factor
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ABSTRACT: Compact lasers that can produce a range of beam patterns are important for progress in several areas, including the improvement of optical tweezers, ultra-high-density optical memory and microfluidics. Here we engineer photonic crystals to generate semiconductor lasers that produce a range of beam patterns while maintaining stable single-mode oscillation. Our results could contribute to the realization of compact lasers that are capable of producing diverse beam patterns on demand.
Nature 07/2006; 441(7096):946. · 36.28 Impact Factor
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Takayuki Okano,
Takayuki Nakagawa,
Tsuyoshi Endo,
Tae-Soo Kim,
Tomoko Kita,
Tetsuya Tamura,
Masahiro Matsumoto,
Tsunehisa Ohno,
Tatsunori Sakamoto,
Fukuichiro Iguchi,
Juichi Ito
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ABSTRACT: This study aimed to evaluate the potential of embryonic stem cell-derived neural progenitors for use as transplants for the replacement of the auditory primary neurons, spiral ganglion neurons. Mouse embryonic stem cell-derived neural progenitors were implanted into the base of the cochlear modiolus of normal or deafened guinea pigs, which contains spiral ganglion neurons and cochlear nerve fibers. Histological analysis demonstrated the survival and neural differentiation of transplants in the cochlear modiolus and active neurite outgrowth of transplants toward host peripheral or central auditory systems. Functional assessments indicated the potential of transplanted embryonic stem cell-derived neural progenitors to elicit the functional recovery of damaged cochleae. These findings support the hypothesis that transplantation of embryonic stem cell-derived neural progenitors can contribute to the functional restoration of spiral ganglion neurons.
Neuroreport 12/2005; 16(17):1919-22. · 1.66 Impact Factor
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ABSTRACT: The generation of superoxide has been implicated as a cause of cochlear damage from excessive noise. Cu/Zn superoxide dismutase (SOD1) generally will protect against superoxide-mediated tissue injury but protection by this enzyme against noise trauma is controversial. This study assessed auditory function in C57BL/6 mice overexpressing SOD1 or treated with lecithinized SOD1 (PC-SOD1). Noise exposure caused significantly higher threshold shifts in PC-SOD1-treated animals than physiological saline-treated animals. Cochlear tissues of PC-SOD1-treated animals exhibited significant elevation of the levels in the SOD activity, not in the catalase activity, in comparison with those of saline-treated animals. Likewise, transgenic mice overexpressing SOD1 tended to suffer higher threshold shifts than nontransgenic littermates from noise exposure. The findings indicate that increasing SOD1 enhances auditory dysfunction following noise exposure.
Free Radical Biology and Medicine 03/2005; 38(4):492-8. · 5.42 Impact Factor
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ABSTRACT: We achieved room temperature continuous wave operation of a surface-emitting two-dimensional photonic crystal diode laser by current injection. This is the first time ever that room temperature continuous wave operation of a photonic crystal diode laser has been realized. This laser features single mode oscillation over a large area, which is impossible for conventional lasers. In this work, we optimized the epitaxial layer composition for better carrier confinement and clarified the relationship between the diameter of the air holes in the photonic crystal and the threshold current of the laser in order to estimate the optimized threshold current.
Optics Express 05/2004; 12(8):1562-8. · 3.59 Impact Factor
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