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.

Keywords: Development; Direct conversion; Drug discovery; Epigenetics; Hair cell regeneration; Hearing loss.

Fig. 1

Diagram (cross section) of the mature cochlear organ of Corti, illustrating the major sensory and non-sensory cell types. IHC: inner hair cell; OHC: outer hair cell; IPhC: inner phalangeal cell; IBC: inner border cell; PC: pillar cell; DC: Deiters’ cell. Lgr5+ cells at neonatal age are highlighted with pink color.

Fig. 2

Examples of direct lineage conversion in other mammalian regenerative systems (A) and in the cochlea (B). The original differentiated cells (at left) were converted to another differentiated cell type (at right). The lineage-specific transcription factors are listed for each conversion.

Fig. 3

Modified “Waddington landscape” for cochlear HC development and regeneration. The original (shaded) cell at the top of the “mountain” represents a zygotic cell. Below, along the “valley,” is an ES/iPS cell representing a pluripotent embryonic stem cell or induced pluripotent stem cell that can give rise to an otic progenitor cell (PC), which in turn gives rise to either a supporting cell (SC) or a hair cell (HC) by following the normal developmental paths (blue arrows). A differentiated fibroblast (Fb) can be reversely converted to iPS by the four Yamanaka factors, following an “uphill” path (green arrows) as opposed to the normal “downhill” developmental path. Importantly, the direct conversion of an SC to an HC takes a path (red arrows) that differs from that of indirect conversion in order to avoid the PC state; there is, therefore, a unique, hybrid cell type (red cell) that is different from a PC or ES/iPS.

Fig. 4

Possible epigenetic regulatory mechanisms during HC regeneration. The compact chromatin structure becomes accessible to transcriptional mechanisms by histone modification, including methylation (Me) and acetylation (Ac), and chromatin remodeler binding. Pioneer TFs are able to interact with the condensed DNA and facilitate the targeting of other TFs. DNA methylation also controls the initiation of transcription.