Hair Cell Regeneration: From Animals to Humans.

Cochlear hair cells convert sound into electrical signals that are relayed via the spiral ganglion neurons to the central auditory pathway. Hair cells are vulnerable to damage caused by excessive noise, aging, and ototoxic agents. Non-mammals can regenerate lost hair cells by mitotic regeneration and direct transdifferentiation of surrounding supporting cells.

Selection of viral capsids and promoters affects the efficacy of rescue of -deficient cochlea.

Adeno-associated virus (AAV)-mediated gene transfer has shown promise in rescuing mouse models of genetic hearing loss, but how viral capsid and promoter selection affects efficacy is poorly characterized. Here, we tested combinations of AAVs and promoters to deliver , mutations in which are associated with hearing loss in humans. mice display severe cochlear hair cell degeneration, loss of auditory brainstem responses, and delayed loss of spiral ganglion neurons.

Lineage-tracing and translatomic analysis of damage-inducible mitotic cochlear progenitors identifies candidate genes regulating regeneration.

Cochlear supporting cells (SCs) are glia-like cells critical for hearing function. In the neonatal cochlea, the greater epithelial ridge (GER) is a mitotically quiescent and transient organ, which has been shown to nonmitotically regenerate SCs. Here, we ablated Lgr5+ SCs using Lgr5-DTR mice and found mitotic regeneration of SCs by GER cells in vivo.

Mutations Linked to Hearing Loss Exhibit Differential Trafficking and Functional Defects as Revealed in Cochlear-Relevant Cells.

gene (that encodes Cx26) mutations are causal of hearing loss highlighting the importance of Cx26-based channel signaling amongst the supporting cells in the organ of Corti. While the majority of these mutations are inherited in an autosomal recessive manner, others are inherited in an autosomal dominant manner and lead to syndromic hearing loss as well as skin diseases. To assess if common or divergent mechanisms are at the root of -linked hearing loss, we expressed several mutants in cochlear-relevant HEI-OC1 cells derived from the developing organ of Corti.

The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss.

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by ) and Cx30 () are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss.

Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss.

Given the importance of connexin43 (Cx43, encoded by ) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express mutations resulting in mild or severe loss of Cx43 function. Although Cx43 mutant mice, with ∼50% Cx43 channel function, did not have any hearing loss, Cx43 mutant mice, with ∼20% Cx43 channel function, had severe hearing loss.

Differential effects of pannexins on noise-induced hearing loss.

Hearing loss, including noise-induced hearing loss, is highly prevalent and severely hinders an individual's quality of life, yet many of the mechanisms that cause hearing loss are unknown. The pannexin (Panx) channel proteins, Panx1 and Panx3, are regionally expressed in many cell types along the auditory pathway, and mice lacking Panx1 in specific cells of the inner ear exhibit hearing loss, suggesting a vital role for Panxs in hearing. We proposed that Panx1 and/or Panx3 null mice would exhibit severe hearing loss and increased susceptibility to noise-induced hearing loss.