Abstract
Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27Kip1 and p21Cip1 expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells.
Highlights
The very limited capacity of the inner ear sensory epithelial cells to proliferate either naturally or following traumas is a critical barrier for hair cell regeneration in mammals
A large part of hair cells were lost by 7 days in vitro (DIV), the extent of this loss being variable between explants (Fig. 1B9)
Hair cell loss did not impair supporting cell’s survival, based on the lack of cells with DNA fragmentation (ApopTag Kit) that marks apoptotic death. Based on these results and on the fact that the platform for therapeutic approaches is a sensory epithelium with hair cell loss, we considered that our adult utricular explants represent a good model for a lesioned sensory epithelium
Summary
The very limited capacity of the inner ear sensory epithelial cells to proliferate either naturally or following traumas is a critical barrier for hair cell regeneration in mammals. Vestibular hair cells forced into S phase can resist acute death, and their DNA is damaged and they are arrested in the cell cycle, with an apparent deathprone ultimate fate [6]. Non-mammalian species possess a natural regenerative capacity in their inner ears; their supporting cells can divide and transdifferentiate into new hair cells, leading to restoration of hearing and balance functions [9,10]. Because of this remarkably different capacity for sensory cell regeneration, there is considerable interest in understanding the molecular mechanisms underlying the restrictions in proliferation in mammalian supporting cells
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