Abstract
Functional hair cell regeneration in the adult mammalian inner ear remains challenging. This study aimed to study the function of new hair cells induced by a DNA demethylating agent 5-azacytidine. Adult mice were deafened chemically, followed by injection of 5-azacytidine or vehicle into the inner ear. Functionality of regenerated hair cells was evaluated by expression of hair cell proteins, auditory brainstem response (ABR), and distortion-product otoacoustic emission (DPOAE) tests for 6 weeks. In the vehicle-treated group, no cells expressed the hair cell-specific protein myosin VIIa in the cochlea, whereas numerous myosin VIIa-expressing cells were found in the 5-azacytidine-treated cochlea, suggesting the regeneration of auditory hair cells. Moreover, regenerated hair cells were co-labeled with functional proteins espin and prestin. Expression of ribbon synapse proteins suggested synapse formation between new hair cells and neurons. In hearing tests, progressive improvements in ABR [5–30 dB sound pressure level (SPL)] and DPOAE (5–20 dB) thresholds were observed in 5-azacytidine-treated mice. In vehicle-treated mice, there were <5 dB threshold changes in hearing tests. This study demonstrated the ability of 5-azacytidine to promote the functional regeneration of auditory hair cells in a mature mouse model via DNA demethylation, which may provide insights into hearing regeneration using an epigenetic approach.
Highlights
According to the WHO, more than 1.5 billion people experience various extents of hearing disorders in the world (World Health Organization, 2021), which largely attribute to auditory hair cell loss and dysfunction
Myosin VIIa-expressing hair cells were observed in the 5-aza-treated mice (Figures 1B,C), confirming hair cells regeneration induced by 5-aza
All the myosin VIIaexpressing hair cells were colabeled with espin (Figure 1B), indicating the expression of hair bundle proteins in these new hair cells
Summary
According to the WHO, more than 1.5 billion people experience various extents of hearing disorders in the world (World Health Organization, 2021), which largely attribute to auditory hair cell loss and dysfunction. Inner hair cells transfer auditory information to spiral ganglion neurons via hair cell ribbon synapses. The neurotransmission between inner hair cells and spiral ganglion neurons involves C-terminal-binding proteins (CtBPs) family of transcriptional corepressor C-terminal-binding protein 2 (CtBP2) expressed at the presynaptic ribbon structure (Nouvian et al, 2006; Matthews and Fuchs, 2010; Uthaiah and Hudspeth, 2010; Liberman et al, 2011) and glutamate receptor 2 (GluR2) as one of the postsynaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (Nouvian et al, 2006; Uthaiah and Hudspeth, 2010; Liberman et al, 2011). In the complex mammalian auditory system, the functionality of hair cells is carried out by the stereocilia of hair bundles, which consist of a variety of proteins, including actin cross-linking proteins, such as espin (Hudspeth, 1989, 2008; Bartles, 2000), as well as the abovementioned functional proteins to detect sound stimulation and transfer signals to spiral ganglion neurons. A successful hair cell regeneration includes the reconstitution of structure and morphology, and the regeneration of hair cell functional proteins and synaptic connections
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