Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function

Kopke, Richard D.; Jackson, Ronald L.; Li, Geming; Rasmussen, Mark D.; Hoffer, Michael E.; Frenz, Dorothy A.; Costello, Michael; Schultheiss, Peter; Water, Thomas R. Van De

doi:10.1073/pnas.101120898

Cited by 61 publications

(38 citation statements)

References 49 publications

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“…Since it is currently unknown how many new hair cells would be required to noticeably restore function in a damaged crista, the stimulation of hair cell regeneration by DAPT treatment that we have demonstrated may have some therapeutic relevance (Kopke et al 2001). Though very promising, the number of hair cells generated here is likely insufficient to fully repair a damaged organ, which is also true of all other mammalian vestibular regeneration to date Warchol et al 1993;Rubel et al 1995;Tanyeri et al 1995;Li and Forge 1997;Lopez et al 2003;Kawamoto et al 2009;Lin et al 2011;Golub et al 2012;Jung et al 2013).…”

Section: Fig 8 Examples Of Lineage Traced Transitional Cells (Tc) mentioning

confidence: 94%

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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Balance disorders caused by hair cell loss in the sensory organs of the vestibular system pose a significant health problem worldwide, particularly in the elderly. Currently, this hair cell loss is permanent as there is no effective treatment. This is in stark contrast to nonmammalian vertebrates who robustly regenerate hair cells after damage. This disparity in regenerative potential highlights the need for further manipulation in order to stimulate more robust hair cell regeneration in mammals. In the utricle, Notch signaling is required for maintaining the striolar support cell phenotype into the second postnatal week. Notch signaling has further been implicated in hair cell regeneration after damage in the mature utricle. Here, we investigate the role of Notch signaling in the mature mammalian cristae in order to characterize the Notch-mediated regenerative potential of these sensory organs. For these studies, we used the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT), in conjunction with a method we developed to culture cristae in vitro. In postnatal and adult cristae, we found that 5 days of DAPT treatment resulted in a downregulation of the Notch effectors Hes1 and Hes5 and also an increase in the total number of Gfi1 + hair cells. Hes5, as reported by Hes5-GFP, was downregulated specifically in peripheral support cells. Using lineage tracing with proteolipid protein (PLP)/CreER;mTmG mice, we found that these hair cells arose through transdifferentiation of support cells in cristae explanted from mice up to 10 weeks of age. These transdifferentiated cells arose without proliferation and were capable of taking on a hair cell morphology, migrating to the correct cell layer, and assembling what appears to be a stereocilia bundle with a long kinocilium. Overall, these data show that Notch signaling is active in the mature cristae and suggest that it may be important in maintaining the support cell fate in a subset of peripheral support cells.

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Section: Fig 8 Examples Of Lineage Traced Transitional Cells (Tc) mentioning

confidence: 94%

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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“…Therefore, histological regeneration and functional recovery must be induced, for example with growth factors, neurotrophic treatment and gene expression profiling, as has already been shown in several studies [Kopke et al, 2001;Xu et al, 2012;Brigande and Heller, 2013;Jung et al, 2013]. The question remains whether end-organ function recovers after (induced) regeneration of hair cells.…”

Section: Future Considerationsmentioning

confidence: 99%

“…The function of vestibular organs has also been studied after induced regeneration [Kopke et al, 2001;Staecker et al, 2007]. Kopke et al [2001] assessed hair cell function using vestibulo-ocular reflexes in guinea pigs after the vestibules were lesioned with gentamicin.…”

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confidence: 99%

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Does Vestibular End-Organ Function Recover after Gentamicin-Induced Trauma in Guinea Pigs?

Bremer

Versnel²,

Hendriksen³

et al. 2014

Audiol Neurotol

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Until 1993 it was commonly accepted that regeneration of vestibular hair cells was not possible in mammals. Two histological studies then showed structural evidence for spontaneous regeneration of vestibular hair cells after gentamicin treatment. There is less evidence for functional recovery going along with this regenerative process; in other words, do regenerated hair cells function adequately? This study aims to address this question, and in general evaluates whether spontaneous functional recovery may occur, in the short or long term, in mammals after ototoxic insult. Guinea pigs were treated with gentamicin for 10 consecutive days at a daily dose of 125 mg/kg body weight. Survival times varied from 1 day to 16 weeks. Vestibular short-latency evoked potentials (VsEPs) to linear acceleration pulses were recorded longitudinally to assess otolith function. After the final functional measurements we performed immunofluorescence histology for hair cell counts. Auditory brainstem responses (ABRs) to click stimuli were recorded to assess cochlear function. As intended, gentamicin treatment resulted in significant loss of utricular hair cells and accompanying declines in VsEPs. Hair cell counts 8 or 16 weeks after treatment did not significantly differ from counts after shorter survival periods. Maximal functional loss was achieved 1-4 weeks after treatment. After this period, only 2 animals showed recovery of VsEP amplitude - all other animals did not reveal signs of regeneration or recovery. In contrast, after initial ABR threshold shifts there was a small but significant recovery. We conclude that spontaneous recovery of otolith function, in contrast to cochlear function, is very limited in guinea pigs. These results support the concept of intratympanic gentamicin treatment where gentamicin is used for chemoablation of the vestibular sensory epithelia.

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“…Genetic and trophic factor manipulations have enhanced repair processes of inner ear neurosensory epithelium [Kopke et al, 2001b;Izumikawa et al, 2005]. Also, new methods have been tested for inner ear drug delivery including middle ear perfusion, use of catheters and wicks for round window membrane (RWM), cochlea, and vestibule [Kopke et al, 2001a;Jones et al, 2004;Izumikawa et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

Magnetic Nanoparticles: Inner Ear Targeted Molecule Delivery and Middle Ear Implant

et al. 2006

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Superparamagnetic iron oxide nanoparticles (SNP) composed of magnetite (Fe₃O₄) were studied preliminarily as vehicles for therapeutic molecule delivery to the inner ear and as a middle ear implant capable of producing biomechanically relevant forces for auditory function. Magnetite SNP were synthesized, then encapsulated in either silica or poly (D,L,-Lactide-co-glycolide) or obtained commercially with coatings of oleic acid or dextran. Permanent magnetic fields generated forces sufficient to pull them across tissue in several round window membrane models (in vitrocell culture, in vivo rat and guinea pig, and human temporal bone) or to embed them in middle ear epithelia. Biocompatibility was investigated by light and electron microscopy, cell culture kinetics, and hair cell survival in organotypic cell culture and no measurable toxicity was found. A sinusoidal magnetic field applied to guinea pigs with SNP implanted in the middle ear resulted in displacements of the middle ear comparable to 90 dB SPL.

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Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function

Cited by 61 publications

References 49 publications

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Does Vestibular End-Organ Function Recover after Gentamicin-Induced Trauma in Guinea Pigs?

Magnetic Nanoparticles: Inner Ear Targeted Molecule Delivery and Middle Ear Implant

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