Quo vadis, hair cell regeneration?

Abstract

Hearing loss is a global health problem with profound socioeconomic impact. We contend that acquired hearing loss is mainly a modern disorder caused by man-made noise and modern drugs, among other causes. These factors, combined with increasing lifespan, have exposed a deficit in cochlear self-regeneration that was irrelevant for most of mammalian evolution. Nevertheless, the mammalian cochlea has evolved from phylogenetically older structures, which do have the capacity for self-repair. Moreover, nonmammalian vertebrates can regenerate auditory hair cells that restore sensory function. We will offer a critical perspective on recent advances in stem cell biology, gene therapy, cell cycle regulation and pharmacotherapeutics to define and validate regenerative medical interventions for mammalian hair cell loss. Although these advances are promising, we are only beginning to fully appreciate the complexity of the many challenges that lie ahead.

Figure 1

Conceptual drawings of the normal, damaged and repaired organ of Corti. (a) In the normal organ of Corti, movements of the basilar membrane are relayed by means of hinging near the tunnel of Corti and shearing motions between outer hair cells (OHCs) and the tectorial membrane. The connections of OHC stereocilia with the tectorial membrane are essential for proper function of the cochlear amplifier. All these parts of the organ of Corti must be in appropriate mechanical correlation with one another to ensure proper stimulation of the inner hair cells (IHCs). (b) Complete loss of IHCs and OHCs, shortly after a toxic insult. (c) Collapse of the tunnel of Corti and dedifferentiation of the supporting cells. (d) Hypothetical reseeding of generic hair cells in the damaged organ of Corti epithelium. It is unclear whether a connection with the tectorial membrane will re-form, how far it will stretch over the new hair cell area and whether the hair cells will be appropriately stimulated by movements of the basilar membrane.

Figure 2

Proliferation and hair cell differentiation from supporting cells. (a) Isolation of stem cells and supporting cells from the organ of Corti. (b) Hair cell differentiation in sphere-derived cultures happens when spheres attach onto substrate, forming islands of cells. Hair cell marker–positive cells (green) differentiate in these islands and appear to sit on top of cells that express supporting cell markers. (c) Alternatively, proliferating supporting cells, cultured with embryonic mesenchymal cells, exit the cell cycle and differentiate into hair cell marker–positive cells. (d) Supporting cells of the adult organ of Corti do not proliferate.