Manipulating cell fate in the cochlea: a feasible therapy for hearing loss

Abstract

Mammalian auditory hair cells do not spontaneously regenerate, unlike hair cells in lower vertebrates, including fish and birds. In mammals, hearing loss due to the loss of hair cells is permanent and intractable. Recent studies in the mouse have demonstrated spontaneous hair cell regeneration during a short postnatal period, but this regenerative capacity is lost in the adult cochlea. Reduced regeneration coincides with a transition that results in a decreased pool of progenitor cells in the cochlear sensory epithelium. Here, we review the signaling cascades involved in hair cell formation and morphogenesis of the organ of Corti in developing mammals, the changing status of progenitor cells in the cochlea, and the regeneration of auditory hair cells in adult mammals.

Keywords: cell replacement; hair cells; hearing loss; sensory systems.

Fig. 1. Schematic of Notch signaling in the developing cochlea

During differentiation of sensory epithelium in the mouse cochlea, a thickened area that expresses Sox2 is specified by embryonic day 12 (E12) (a). The cells destined to become the cochlear sensory epithelium exit the cell cycle in a region termed the zone of non-proliferating cells marked by the expression of cell cycle inhibitor. p27Kip1 (b). A master gene for hair cell differentiation, Atoh1, is observed within this area (c). Emerging Atoh1-positive cells (blue) start to express Notch ligands including jagged 2 and interact with neighboring cells through Notch signal-mediated “lateral inhibition” (d, e). In the surrounding cells, hair cell genes are shut down through the competition of Hes and Atoh1 (e). Therefore, the cells adjacent to hair cells differentiate into supporting cells, resulting in a checkerboard arrangement of hair cells and supporting cells (f). (ZNPC: Zone of non-proliferating cells; J2: jagged 2; N1: Notch 1; PS: Presenilin; NICD: Notch intracellular domain)

Fig. 2. Scanning electron microscopy (SEM) of the organ of Corti after LY411575 administration

SEM images of the organ of Corti of young adult mice without treatment (a,d,e) and after acoustic trauma with (c,f,g) and without (b) administration of LY411575 to regenerate hair cells. Note that the cells in the inner pillar cell region (adjacent to inner hair cells) had disorganized “immature” stereociliary bundles (c, f), while bundles in the outer hair cells were apparently normal (g).

Fig. 3. Tracing the lineage of regenerated hair cells

Prior to noise exposure, supporting cells were labeled in green by administration of tamoxifen to activate CreER (under a Sox2 promoter) in supporting cells Following LY411575 treatment after ototoxic insult, newly generated hair cells derived from supporting cells retained a green label, in contrast to the surviving hair cells which remained red.

Fig. 4. Regenerated hair cells

Hair cells and supporting cells were labeled by anti myosin VIIa (green) and anti Sox2 (blue) antibodies, respectively (a). hair cells number increased by approximately the same amount as the supporting cells number decreased. Supporting cell lineage was traced in green and other cells in red in Sox2-CreER; mT/mG double transgenic mice. (b). As described in Fig. 2, hair cells (marked by arrowheads) transdifferentiated from supporting cells were green, while surviving hair cells after noise exposure were red. Some of the green hair cells (right panel in the Z-stack) shown in the diagram (c) extended to the basilar membrane (arrow). The figure is reproduced with permission from Figure 4 and 5, Mizutari et al., Neuron Vol. 77 Issue 1.