Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?

Abstract

Noise-induced hearing loss (NIHL) affects a large number of military personnel and civilians. Regenerating inner-ear cochlear hair cells (HCs) is a promising strategy to restore hearing after NIHL. In this review, we first summarize recent transcriptome profile analysis of zebrafish lateral lines and chick utricles where spontaneous HC regeneration occurs after HC damage. We then discuss recent studies in other mammalian regenerative systems such as pancreas, heart and central nervous system. Both spontaneous and forced HC regeneration occurs in mammalian cochleae in vivo involving proliferation and direct lineage conversion. However, both processes are inefficient and incomplete, and decline with age. For direct lineage conversion in vivo in cochleae and in other systems, further improvement requires multiple factors, including transcription, epigenetic and trophic factors, with appropriate stoichiometry in appropriate architectural niche. Increasing evidence from other systems indicates that the molecular paths of direct lineage conversion may be different from those of normal developmental lineages. We therefore hypothesize that HC regeneration does not have to follow HC development and that epigenetic memory of supporting cells influences the HC regeneration, which may be a key to successful cochlear HC regeneration. Finally, we discuss recent efforts in viral gene therapy and drug discovery for HC regeneration. We hope that combination therapy targeting multiple factors and epigenetic signaling pathways will provide promising avenues for HC regeneration in humans with NIHL and other types of hearing loss.

Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System

“…In the developing utricle, specified HCs first acquire bundles and mechanotransduction and subsequently basolateral potassium currents and nerve terminals characteristic of HC subtype specialization (Geleoc et al, 2004). Therefore, unlike developing HCs, apical bundles in regenerating HCs fail to mature despite grossly normal synaptic elements and innervation (Atkinson et al, 2015; Zheng and Zuo, 2017; Wang et al, 2019). Such discrepancies in the degrees of maturation of bundles and basolateral features were previously observed in ectopic HCs in the neonatal and mature cochlea and HCs derived from embryonic stem cells (Gubbels et al, 2008; Oshima et al, 2010; Walters et al, 2017).…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…For example, topical application of IGF1 to the middle ear was used to treat sudden sensorineural hearing loss in humans, and some treated individuals showed improvements of 10 to 30 dB for tested frequencies as compared to controls . Hair cell regeneration in response to application of growth factors and by inhibition of specific signaling pathways is also being explored . For example, an inhibitor of NOTCH signaling is in phase II clinical trial for treatment of sensorineural moderate to severe hearing loss .…”

“…103,112 Hair cell regeneration in response to application of growth factors and by inhibition of specific signaling pathways is also being explored. 113 For example, an inhibitor of NOTCH signaling is in phase II clinical trial for treatment of sensorineural moderate to severe hearing loss. 21 As signaling pathways are involved with differentiation, proliferation, maintenance and regeneration processes, greater understanding of the in vivo ligands, receptors, protein partners and the modulation of their expression may provide opportunities to rebuild a properly patterned and functional adult human inner ear.…”

Standardized Methodologies to Utilize Exosome Treatment as Potential Nano Substances in Hearing Loss

“…Hearing loss is reported as a permanent hearing impairment because of its high prevalence and few known treatment and recovery methods [5,6]. The number of elderly people has been increasing at a rate of 4.8% per year on average, more than half of those in their 60s are among 53.6% of the total elderly population, and the rate of hearing-impaired individuals in their 10s and 30s has also reached up to 19.2% because of the increase in the number of smartphones, which has also led to severe social isolation [7][8][9].…”