The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Yehoash Raphael - One of the best experts on this subject based on the ideXlab platform.
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p27Kip1 deficiency causes Organ of Corti pathology and hearing loss
Hearing Research, 2006Co-Authors: Sho Kanzaki, Lisa A. Beyer, Donald L. Swiderski, Masahiko Izumikawa, Timo Stöver, Kohei Kawamoto, Yehoash RaphaelAbstract:Abstract p27Kip1 (p27) has been shown to inhibit several cyclin-dependent kinase molecules and to play a central role in regulating entry into the cell cycle. Once hair cells in the cochlea are formed, p27 is expressed in non-sensory cells of the Organ of Corti and prevents their re-entry into the cell cycle. In one line of p27 deficient mice (p27−/−), cell division in the Organ of Corti continues past its normal embryonic time, leading to continual production of cells in the Organ of Corti. Here we report on the structure and function of the inner ear in another line of p27 deficient mice originating from the Memorial Sloan-Kettering Cancer Center. The deficiency in p27 expression of these mice is incomplete, as they retain expression of amino acids 52–197. We determined that mice homozygote for this mutation had severe hearing loss and their Organ of Corti exhibited an increase in the number of inner and outer hair cells. There also was a marked increase in the number of supporting cells, with severe pathologies in pillar cells. These data show similarities between this p27Kip1 mutation and another, previously reported null allele of this gene, and suggest that reducing the inhibition on the cell cycle in the Organ of Corti leads to pathology and dysfunction. Manipulations to regulate the time and place of p27 inhibition will be necessary for inducing functionally useful hair cell regeneration.
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p27(Kip1) deficiency causes Organ of Corti pathology and hearing loss.
Hearing research, 2006Co-Authors: Sho Kanzaki, Lisa A. Beyer, Donald L. Swiderski, Masahiko Izumikawa, Timo Stöver, Kohei Kawamoto, Yehoash RaphaelAbstract:p27(Kip1) (p27) has been shown to inhibit several cyclin-dependent kinase molecules and to play a central role in regulating entry into the cell cycle. Once hair cells in the cochlea are formed, p27 is expressed in non-sensory cells of the Organ of Corti and prevents their re-entry into the cell cycle. In one line of p27 deficient mice (p27(-/-)), cell division in the Organ of Corti continues past its normal embryonic time, leading to continual production of cells in the Organ of Corti. Here we report on the structure and function of the inner ear in another line of p27 deficient mice originating from the Memorial Sloan-Kettering Cancer Center. The deficiency in p27 expression of these mice is incomplete, as they retain expression of amino acids 52-197. We determined that mice homozygote for this mutation had severe hearing loss and their Organ of Corti exhibited an increase in the number of inner and outer hair cells. There also was a marked increase in the number of supporting cells, with severe pathologies in pillar cells. These data show similarities between this p27(Kip1) mutation and another, previously reported null allele of this gene, and suggest that reducing the inhibition on the cell cycle in the Organ of Corti leads to pathology and dysfunction. Manipulations to regulate the time and place of p27 inhibition will be necessary for inducing functionally useful hair cell regeneration.
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Gene transfer into supporting cells of the Organ of Corti
Hearing research, 2002Co-Authors: Shin Ichi Ishimoto, Sho Kanzaki, Kohei Kawamoto, Yehoash RaphaelAbstract:To utilize the rapidly accumulating genetic information for developing new therapeutic technologies for inner ear disease, it is necessary to design technologies for expressing transgenes in the inner ear, especially in the Organ of Corti. We examined the outcome of an adenovirus gene transfer into the Organ of Corti via the scala media in guinea pigs. The transgene insert is the bacterial lacZ gene driven by a cytomegalovirus promoter. We demonstrate that the inoculation is detrimental to the hair cells that surround the site of inoculation, but the supporting cells in the Organ of Corti survive and retain the ability to express the reporter transgene β-gal. The ability to deliver transgenes that are expressed in the supporting cells is an important step in the development of clinically applicable treatments that involve hair cell regeneration.
Jong-hoon Nam - One of the best experts on this subject based on the ideXlab platform.
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mechanically facilitated micro fluid mixing in the Organ of Corti
Scientific Reports, 2020Co-Authors: Mohammad Shokrian, Catherine Knox, Douglas H Kelley, Jong-hoon NamAbstract:The cochlea is filled with two lymphatic fluids. Homeostasis of the cochlear fluids is essential for healthy hearing. The sensory epithelium called the Organ of Corti separates the two fluids. Corti fluid space, extracellular fluid space within the Organ of Corti, looks like a slender micro-tube. Substantial potassium ions are constantly released into the Corti fluid by sensory receptor cells. Excess potassium ions in the Corti fluid are resorbed by supporting cells to maintain fluid homeostasis. Through computational simulations, we investigated fluid mixing within the Corti fluid space. Two assumptions were made: first, there exists a longitudinal gradient of potassium ion concentration; second, outer hair cell motility causes Organ of Corti deformations that alter the cross-sectional area of the Corti fluid space. We hypothesized that mechanical agitations can accelerate longitudinal mixing of Corti fluid. Corti fluid motion was determined by solving the Navier-Stokes equations incorporating nonlinear advection term. Advection-diffusion equation determined the mixing dynamics. Simulating traveling boundary waves, we found that advection and diffusion caused comparable mixing when the wave amplitude and speed were 25 nm and 7 m/s, respectively. Higher-amplitude and faster waves caused stronger advection. When physiological traveling waves corresponding to 70 dB sound pressure level at 9 kHz were simulated, advection speed was as large as 1 mm/s in the region basal to the peak responding location. Such physiological agitation accelerated longitudinal mixing by more than an order of magnitude, compared to pure diffusion. Our results suggest that fluid motion due to outer hair cell motility can help maintain longitudinal homeostasis of the Corti fluid.
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Interactions between Passive and Active Vibrations in the Organ of Corti In Vitro
Biophysical journal, 2020Co-Authors: Talat Jabeen, Joseph C. Holt, Jonathan R. Becker, Jong-hoon NamAbstract:High sensitivity and selectivity of hearing require an active cochlea. The cochlear sensory epithelium, the Organ of Corti, vibrates because of external and internal excitations. The external stimulation is acoustic pressures mediated by the scala fluids, whereas the internal excitation is generated by a type of sensory receptor cells (the outer hair cells) in response to the acoustic vibrations. The outer hair cells are cellular actuators that are responsible for cochlear amplification. The Organ of Corti is highly structured for transmitting vibrations originating from acoustic pressure and active outer hair cell force to the inner hair cells that synapse on afferent nerves. Understanding how the Organ of Corti vibrates because of acoustic pressure and outer hair cell force is critical for explaining cochlear function. In this study, cochleae were freshly isolated from young gerbils. The Organ of Corti in the excised cochlea was subjected to mechanical and electrical stimulation that are analogous to acoustic and cellular stimulation in the natural cochlea. Organ of Corti vibrations, including those of individual outer hair cells, were measured using optical coherence tomography. Respective vibration patterns due to mechanical and electrical stimulation were characterized. Interactions between the two vibration patterns were investigated by applying the two forms of stimulation simultaneously. Our results show that the interactions could be either constructive or destructive, which implies that the outer hair cells can either amplify or reduce vibrations in the Organ of Corti. We discuss a potential consequence of the two interaction modes for cochlear frequency tuning.
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Active outer hair cell motility can suppress vibrations in the Organ of Corti
2020Co-Authors: Jong-hoon Nam, Talat Jabeen, Joseph C. Holt, Jonathan R. BeckerAbstract:High sensitivity and selectivity of hearing require active cochlea. The cochlear sensory epithelium, the Organ of Corti, vibrates due to external and internal excitations. The external stimulation is acoustic pressures mediated by the scala fluids, while the internal excitation is generated by a type of sensory receptor cells (the outer hair cells) in response to the acoustical vibrations. The outer hair cells are cellular actuators that are responsible for cochlear amplification. The Organ of Corti is highly structured for transmitting vibrations originating from acoustic pressure and active outer hair cell force to the inner hair cells that synapse on afferent nerves. Understanding how the Organ of Corti vibrates due to acoustic pressure and outer hair cell force is critical for explaining cochlear function. In this study, excised cochlear turns were freshly isolated from young gerbils. The Organ of Corti in the excised cochlea was subjected to mechanical and electrical stimulation that are analogous to acoustical and cellular stimulation in the natural cochlea. Organ of Corti vibrations including those of individual outer hair cells were measured using optical coherence tomography. Respective vibration patterns due to mechanical and electrical stimulation were characterized. Interactions between the two vibration patterns were investigated by applying the two forms of stimulation simultaneously. Our results show that the interactions could be either constructive or destructive, which implies that the outer hair cells can either amplify or suppress vibrations in the Organ of Corti. We discuss a potential consequence of the two interaction modes for cochlear frequency tuning.
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Power dissipation in the Organ of Corti
The Journal of the Acoustical Society of America, 2017Co-Authors: Srdjan Prodanovic, Sheryl M. Gracewski, Jong-hoon NamAbstract:In the cochlea, acoustic energy is transmitted toward the apex through the vibrations of a viscoelastic partition known as the Organ of Corti complex. The dimensions of the vibrating structures range from a few hundred micrometers to a few micrometers. Vibrations of micro-structures in viscous fluid are subjected to energy dissipation. Because the viscous dissipation is considered to be detrimental to the function of hearing—sound amplification and frequency tuning, the cochlea is believed to use cellular actuators to overcome the dissipation. We have developed a computational model of the cochlea that incorporates viscous fluid dynamics, Organ of Corti micro-structural mechanics, and electro-physiology of the outer hair cells. The model is validated by comparing with experimental results in the literature, such as the viscoelastic response of the tectorial membrane, and the cochlear input impedance. Using the model, we investigated how dissipation components in the cochlea affect its function. Our result...
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Consequences of Location-Dependent Organ of Corti Micro-Mechanics
2015Co-Authors: Yanju Liu, Sheryl M. Gracewski, Jong-hoon NamAbstract:The cochlea performs frequency analysis and amplification of sounds. The graded stiffness of the basilar membrane along the cochlear length underlies the frequency-location relationship of the mammalian cochlea. The somatic motility of outer hair cell is central for cochlear amplification. Despite two to three orders of magnitude change in the basilar membrane stiffness, the force capacity of the outer hair cell’s somatic motility, is nearly invariant over the cochlear length. It is puzzling how actuators with a constant force capacity can operate under such a wide stiffness range. We hypothesize that the Organ of Corti sets the mechanical conditions so that the outer hair cell’s somatic motility effectively interacts with the media of traveling waves—the basilar membrane and the tectorial membrane. To test this hypothesis, a computational model of the gerbil cochlea was developed that incorporates Organ of Corti structural mechanics, cochlear fluid dynamics, and hair cell electro-physiology. The model simulations showed that the micro-mechanical responses of the Organ of Corti are different along the cochlear length. For example, the top surface of the Organ of Corti vibrated more than the bottom surface at the basal (high frequency) location, but the amplitude ratio was reversed at the apical (low frequency) location. Unlike the basilar membrane stiffness varying by a factor of 1700 along the cochlear length, the stiffness of the Organ of Corti complex felt by the outer hair cell remained between 1.5 and 0.4 times the outer hair cell stiffness. The Y-shaped structure in the Organ of Corti formed by outer hair cell, Deiters cell and its phalange was the primary determinant of the elastic reactance imposed on the outer hair cells. The stiffness and geometry of the Deiters cell and its phalange affected cochlear amplification differently depending on the location.
Neil Segil - One of the best experts on this subject based on the ideXlab platform.
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p27(Kip1) links cell proliferation to morphogenesis in the developing Organ of Corti
Development (Cambridge England), 1999Co-Authors: Ping Chen, Neil SegilAbstract:Strict control of cellular proliferation is required to shape the complex structures of the developing embryo. The Organ of Corti, the auditory neuroepithelium of the inner ear in mammals, consists of two types of terminally differentiated mechanosensory hair cells and at least four types of supporting cells arrayed precisely along the length of the spiral cochlea. In mice, the progenitors of greater than 80% of both hair cells and supporting cells undergo their terminal division between embryonic day 13 (E13) and E14. As in humans, these cells persist in a non-proliferative state throughout the adult life of the animal. Here we report that the correct timing of cell cycle withdrawal in the developing Organ of Corti requires p27(Kip1), a cyclin-dependent kinase inhibitor that functions as an inhibitor of cell cycle progression. p27(Kip1) expression is induced in the primordial Organ of Corti between E12 and E14, correlating with the cessation of cell division of the progenitors of the hair cells and supporting cells. In wild-type animals, p27(Kip1) expression is downregulated during subsequent hair cell differentiation, but it persists at high levels in differentiated supporting cells of the mature Organ of Corti. In mice with a targeted deletion of the p27(Kip1) gene, proliferation of the sensory cell progenitors continues after E14, leading to the appearance of supernumerary hair cells and supporting cells. In the absence of p27(Kip1), mitotically active cells are still observed in the Organ of Corti of postnatal day 6 animals, suggesting that the persistence of p27(Kip1) expression in mature supporting cells may contribute to the maintenance of quiescence in this tissue and, possibly, to its inability to regenerate. Homozygous mutant mice are severely hearing impaired. Thus, p27(Kip1) provides a link between developmental control of cell proliferation and the morphological development of the inner ear.
Sho Kanzaki - One of the best experts on this subject based on the ideXlab platform.
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p27Kip1 deficiency causes Organ of Corti pathology and hearing loss
Hearing Research, 2006Co-Authors: Sho Kanzaki, Lisa A. Beyer, Donald L. Swiderski, Masahiko Izumikawa, Timo Stöver, Kohei Kawamoto, Yehoash RaphaelAbstract:Abstract p27Kip1 (p27) has been shown to inhibit several cyclin-dependent kinase molecules and to play a central role in regulating entry into the cell cycle. Once hair cells in the cochlea are formed, p27 is expressed in non-sensory cells of the Organ of Corti and prevents their re-entry into the cell cycle. In one line of p27 deficient mice (p27−/−), cell division in the Organ of Corti continues past its normal embryonic time, leading to continual production of cells in the Organ of Corti. Here we report on the structure and function of the inner ear in another line of p27 deficient mice originating from the Memorial Sloan-Kettering Cancer Center. The deficiency in p27 expression of these mice is incomplete, as they retain expression of amino acids 52–197. We determined that mice homozygote for this mutation had severe hearing loss and their Organ of Corti exhibited an increase in the number of inner and outer hair cells. There also was a marked increase in the number of supporting cells, with severe pathologies in pillar cells. These data show similarities between this p27Kip1 mutation and another, previously reported null allele of this gene, and suggest that reducing the inhibition on the cell cycle in the Organ of Corti leads to pathology and dysfunction. Manipulations to regulate the time and place of p27 inhibition will be necessary for inducing functionally useful hair cell regeneration.
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p27(Kip1) deficiency causes Organ of Corti pathology and hearing loss.
Hearing research, 2006Co-Authors: Sho Kanzaki, Lisa A. Beyer, Donald L. Swiderski, Masahiko Izumikawa, Timo Stöver, Kohei Kawamoto, Yehoash RaphaelAbstract:p27(Kip1) (p27) has been shown to inhibit several cyclin-dependent kinase molecules and to play a central role in regulating entry into the cell cycle. Once hair cells in the cochlea are formed, p27 is expressed in non-sensory cells of the Organ of Corti and prevents their re-entry into the cell cycle. In one line of p27 deficient mice (p27(-/-)), cell division in the Organ of Corti continues past its normal embryonic time, leading to continual production of cells in the Organ of Corti. Here we report on the structure and function of the inner ear in another line of p27 deficient mice originating from the Memorial Sloan-Kettering Cancer Center. The deficiency in p27 expression of these mice is incomplete, as they retain expression of amino acids 52-197. We determined that mice homozygote for this mutation had severe hearing loss and their Organ of Corti exhibited an increase in the number of inner and outer hair cells. There also was a marked increase in the number of supporting cells, with severe pathologies in pillar cells. These data show similarities between this p27(Kip1) mutation and another, previously reported null allele of this gene, and suggest that reducing the inhibition on the cell cycle in the Organ of Corti leads to pathology and dysfunction. Manipulations to regulate the time and place of p27 inhibition will be necessary for inducing functionally useful hair cell regeneration.
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Gene transfer into supporting cells of the Organ of Corti
Hearing research, 2002Co-Authors: Shin Ichi Ishimoto, Sho Kanzaki, Kohei Kawamoto, Yehoash RaphaelAbstract:To utilize the rapidly accumulating genetic information for developing new therapeutic technologies for inner ear disease, it is necessary to design technologies for expressing transgenes in the inner ear, especially in the Organ of Corti. We examined the outcome of an adenovirus gene transfer into the Organ of Corti via the scala media in guinea pigs. The transgene insert is the bacterial lacZ gene driven by a cytomegalovirus promoter. We demonstrate that the inoculation is detrimental to the hair cells that surround the site of inoculation, but the supporting cells in the Organ of Corti survive and retain the ability to express the reporter transgene β-gal. The ability to deliver transgenes that are expressed in the supporting cells is an important step in the development of clinically applicable treatments that involve hair cell regeneration.
Philippe Lefebvre - One of the best experts on this subject based on the ideXlab platform.
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Epithelial supporting cells can differentiate into outer hair cells and Deiters' cells in the cultured Organ of Corti
Cellular and Molecular Life Sciences, 2002Co-Authors: B Malgrange, Marc Thiry, Laurent Nguyen, Gustave Moonen, T. R. Van De Water, Philippe LefebvreAbstract:The Organ of Corti is a complex structure containing a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs), supported respectively by one row of inner phalangeal cells and three rows of Deiters' cells. When fetal rat Organ of Corti explants are cultured, supernumerary OHCs and supernumerary Deiters' cells are produced, without any additional cell proliferation. Analysis of semi- and ultrathin sections revealed that supernumerary OHCs are produced at the distal edge of the Organ of Corti. Quantitative analysis of cell types present in the Organ of Corti demonstrates that when the number of OHCs increases: (i) the total number of cells remains constant; (ii) the number of Deiters' cells increases; (iii) the number of tectal cells decreases and of Hensen's cells decreases. Using specific HC markers, i.e. jagged2 (Jag2) and Math1, we showed that in addition to existing OHCs, supernumerary OHCs, tectal cells and Hensen's cells expressed these markers in embryonic day 19 Organ of Corti explants after 5 days in vitro. The results of this study suggest that Hensen's cells retain the capacity to differentiate into either tectal cells, which differentiate into OHCs, or into undertectal cells which differentiate into Deiters' cells.
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Identification of factors that maintain mammalian outer hair cells in adult Organ of Corti explants.
Hearing Research, 2002Co-Authors: Brigitte Malgrange, Jean Michel Rigo, Paul Coucke, Marc Thiry, Grégory Hans, Laurent Nguyen, Thomas R. Van De Water, Gustave Moonen, Philippe LefebvreAbstract:Both outer hair cells (OHCs) and inner hair cells (IHCs) survive and mature in 3 days old rat Organ of Corti explants cultured for 1 month in a minimal essential medium. In contrast, under the same culture conditions, only IHCs survive in explants from adult guinea pig Organ of Corti while many of the OHCs are lost within the first 48 h. Hair cell counts show OHCs loss to be greater in the lower portion (i.e. middle turn) of the cochlea than at the apex. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) indicates that there is DNA damage in adult OHCs within 8 h of explantation. Treatment of the adult Organ of Corti explants with either actinomycin D (10−7 M) or cycloheximide (10−6 M) prevents most OHC losses. According to these results apoptosis may be the mechanism of OHC loss in adult Organ of Corti explants. Stable membrane potentials recorded from the OHCs in both uncultured and actinomycin D-treated Organ of Corti explants cultured for 72 h demonstrate the functional integrity of these hair cells. OHC losses in the adult guinea pig Organ of Corti cultures can also be prevented by treatment with several of the growth factors tested, i.e. acidic fibroblast growth factor (aFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1), and glial cell-derived neurotrophic factor (GDNF). The results of this study suggest that growth factor therapy may be applicable to the treatment of some hearing disorders.