“Reprogramming by Drug-Like Molecules Leads to Regeneration of Cochlear Hair Cell-Like Cells in Adult Mice”, 2023-05-17 ():
Hearing loss affects millions of people without a single FDA-approved drug for treatment. The loss of the inner ear sensory cells, the hair cells, is considered one of the most common causes of hearing loss that is generally permanent. Such loss cannot be compensated by the terminally differentiated supporting cells, which do not readily transdifferentiate into new hair cells in adult mouse cochleae.
Using single-cell RNAseq, advanced imaging, electrophysiology, and lineage tracing, et al 2023 identified a combination (the cocktail) of drug-like molecules composed of small molecules and siRNAs that effectively reprograms fully mature wild-type supporting cells for hair cell-like cell regeneration in a mouse model with hair cell loss, representing a step forward for hearing restoration by HC regeneration.
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 nontransgenic 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 & 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.