Abstract
Regeneration of mature mammalian inner ear hair cells remains to be a challenge. This study aims to evaluate the ability of DNA methyltransferase (Dnmt) inhibitor 5-azacytidine (5-aza) to generate outer hair cells (OHCs) in a chemically-deafened adult mouse model. 5-aza was administrated into the mouse inner ear via the round window. Immunofluorescence was used to examine the expression of hair cell specific proteins following 5-aza treatment. The results showed that in the chemically-deafened mouse cochlea, new OHCs were found post 5-aza treatment, whereas OHCs were completely lost in saline-treated mice. New hair cells expressed multiple hair cell markers included Myosin VIIa, Pou4f3 and Myosin VI. Newly-generated hair cells presented in three cochlear turns and were able to survive for at least six weeks. The effects of new hair cells generation by 5-aza were concentration dependent. Quantitative PCR study indicates that 5-aza may function through Dnmt1 inhibition. The results of this report suggest that the Dnmt inhibitor 5-aza may promote hair cell regeneration in a chemically-deafened mouse model.
Highlights
Several approaches including gene therapy, cell transplantation and pharmacotherapy have been explored for hair cell regeneration[4]
Because outer hair cells (OHCs) are more sensitive to aminoglycoside[27], we focused on the regeneration of OHCs in the present study
Inner and outer hair cells were damaged in an ototoxicity mouse model
Summary
Several approaches including gene therapy, cell transplantation and pharmacotherapy have been explored for hair cell regeneration[4]. 5-aza was able to increase the expression of hair cell genes and proteins in mouse utricle sensory epithelia-derived progenitor cells in vitro[24]. It is unclear whether the same effects of 5-aza can be applied to in vivo and mature hair cell epithelium. The methods of deafening mice include noise exposure, gene mutation and ototoxic drugs These methods are usually selected according to the nature of the studies. The aim of this research is to determine whether the Dnmt inhibitor is able to stimulate the regeneration of cochlear OHC in the deafened mature mouse inner ear
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