Numerous forms of deafness, including age-related hearing loss, involve either loss of hair cells in the inner ear or loss of their axonal connections to the brain. These cells do not normally regenerate in mammals, and there is some interest in finding a way to bypass the suppression mechanisms that allow growth of hair cells during development but prevent regrowth during adult life. Approaches that show promise in animal studies include stem cell transplants, gene therapies, and small molecules targeting regulatory pathways. Here, researchers report on the ability of a mix of small molecules and siRNAs to produce regeneration of hair cells; an interesting option, but clearly still at a very early stage of development.
Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the non-transgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation.
We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.