Abstract
The mechanism underlying hair cell (HC) regeneration in the mammalian inner ear is still under debate. Understanding what molecules regulate the HC regeneration in mature mammals will be the key to the treatment of the inner ear disorder. Musashi1 (MSI1) is an RNA binding protein associated with asymmetric division and maintenance of stem cell function as a modulator of the Notch-1 signaling pathway. In this study, we investigated the cellular proliferative activity and changes in spatiotemporal pattern of MSI1 expression in the gentamicin (GM)-treated crista ampullaris (CA) in guinea pigs. Although the vestibular HCs in the CA almost disappeared at 14 days after injecting GM in the inner ear, the density of vestibular HCs spontaneously increased by up to 50% relative to controls at 56 days post-GM treatment (PT). The number of the type II HCs was significantly increased at 28 days PT relative to 14 days PT (p < 0.01) while that of type I HCs or supporting cells (SCs) did not change. The number of SCs did not change through the observational period. Administration of bromodeoxyuridine with the same GM treatment showed that the cell proliferation activity was high in SCs between 14 and 28 days PT. The changes in spatiotemporal patterns of MSI1 expression during spontaneous HC regeneration following GM treatment showed that MSI1-immunoreactivity was diffusely spread into the cytoplasm of the SCs during 7–21 days PT whereas the expression of MSI1 was confined to the nucleus of SCs in the other period. The MSI1/MYO7A double-positive cells were observed at 21 days PT. These results suggest that regeneration of vestibular HCs might originate in the asymmetric cell division and differentiation of SCs and that MSI1 might be involved in controlling the process of vestibular HC regeneration.
Highlights
Damage and loss of sensory hair cells (HCs) in the inner ear through aging, exposure to noise, and genetic disorders cause hearing and balance disorders in millions of people each year (Nadol, 1993)
Type I HCs labeled with anti-MYO7A/Pvalb/DAPI and type II HCs labeled with anti-MYO7A/DAPI could both be identified by their more superficially located nuclei than those of supporting cells (SCs) which formed a single row over the basal membrane
Type II HCs increased in density at 56 days post-GM treatment (PT) (82% of the untreated period) and there was no significant difference in density between at the untreated period and at 56 days PT
Summary
Damage and loss of sensory hair cells (HCs) in the inner ear through aging, exposure to noise, and genetic disorders cause hearing and balance disorders in millions of people each year (Nadol, 1993). The mechanism underlying HC regeneration is a large topic of investigation, and generally two different mechanisms have been proposed as spontaneous HC regeneration models; mitotic cell division and non-mitosis-mediated direct transdifferentiation. A study revealed that spontaneous HC regeneration occurred in the neonatal mouse cochlea after damage by genetic methods in vivo, and suggested that regenerated HCs were derived by both mitotic cell division and direct transdifferentiation (Bramhall et al, 2014; Cox et al, 2014). The mechanism underlying spontaneous regenerative process of HCs in the mature mammalian inner ear after damage is still controversial. When the mitotic cell division is involved in the mechanism of regenerative process, it is still unknown whether the type of cell division is symmetric or asymmetric. In an asymmetric division, the stem or progenitor cell generates a copy of itself, which retains self-renewal ability and differentiation potential, and one daughter cell that enters the path of differentiation (Gómez-López et al, 2014)
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