1.Stem Cell-Based Hair Cell Regeneration and Therapy in the Inner Ear.
Jieyu QI ; Wenjuan HUANG ; Yicheng LU ; Xuehan YANG ; Yinyi ZHOU ; Tian CHEN ; Xiaohan WANG ; Yafeng YU ; Jia-Qiang SUN ; Renjie CHAI
Neuroscience Bulletin 2024;40(1):113-126
Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.
Infant, Newborn
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Humans
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Hair Cells, Auditory, Inner/physiology*
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Ear, Inner/physiology*
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Hair Cells, Auditory/physiology*
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Regeneration/genetics*
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Stem Cells
3.Dynamic changes in hair cell ribbon synapse induced by loss of spiral ganglion neurons in mice.
Chinese Medical Journal 2014;127(10):1941-1946
BACKGROUNDPrevious studies have suggested that primary degeneration of hair cells causes secondary degeneration of spiral ganglion neurons (SGNs), but the effect of SGN degeneration on hair cells has not been studied. In the adult mouse inner ear ouabain can selectively and permanently induce the degeneration of type 1 SGNs while leaving type 2 SGNs, efferent fibers, and sensory hair cells relatively intact. This study aimed to investigate the dynamic changes in hair cell ribbon synapse induced by loss of SGNs using ouabain application to the round window niche of adult mice.
METHODSIn the analysis, 24 CBA/CAJ mice aged 8-10 weeks, were used, of which 6 normal mice were used as the control group. After ouabain application in the round window niche 6 times in an hour, ABR threshold shifts at least 30 dB in the three experimental groups which had six mice for 1-week group, six for 1-month group, and six for 3-month group. All 24 animals underwent function test at 1 week and then immunostaining at 1 week, 1 month, and 3 months.
RESULTSThe loss of neurons was followed by degeneration of postsynaptic specializations at the afferent synapse with hair cells. One week after ouabain treatment, the nerve endings of type 1 SGNs and postsynaptic densities, as measured by Na/K ATPase and PSD-95, were affected but not entirely missing, but their partial loss had consequences for synaptic ribbons that form the presynaptic specialization at the synapse between hair cells and primary afferent neurons. Ribbon numbers in inner hair cells decreased (some of them broken and the ribbon number much decreased), and the arrangement of the synaptic ribbons had undergone a dynamic reorganization: ribbons with or without associated postsynaptic densities moved from their normal location in the basal membrane of the cell to a more apical location and the neural endings alone were also found at more apical locations without associated ribbons. After 1 month, when the neural postsynaptic densities had completed their degeneration, most ribbons were lost and the remaining ribbons had no contact with postsynaptic densities; after 3 months, the ribbon synapses were gone except for an occasional remnant of a CtBP2-positive vesicle. Hair cells were intact other than the loss of ribbons (based on immunohistochemistry and DPOAE).
CONCLUSIONThese findings define the effect of SGN loss on the precise spatiotemporal size and location of ribbons and the time course of synaptic degeneration and provide a model for studying plasticity and regeneration.
Animals ; Female ; Hair Cells, Auditory ; cytology ; physiology ; Hair Cells, Auditory, Inner ; cytology ; physiology ; Mice ; Mice, Inbred CBA ; Synapses ; physiology