The challenge of hair cell regeneration

Abstract

Sensory hair cells of the inner ear are responsible for translating auditory or vestibular stimuli into electrical energy that can be perceived by the nervous system. Although hair cells are exquisitely mechanically sensitive, they can be easily damaged by excessive stimulation by ototoxic drugs and by the effects of aging. In mammals, auditory hair cells are never replaced, such that cumulative damage to the ear causes progressive and permanent deafness. In contrast, non-mammalian vertebrates are capable of replacing lost hair cells, which has led to efforts to understand the molecular and cellular basis of regenerative responses in different vertebrate species. In this review, we describe recent progress in understanding the limits to hair cell regeneration in mammals and discuss the obstacles that currently exist for therapeutic approaches to hair cell replacement.

Figure 1

Diagram illustrating two different modes of avian hair cell regeneration. After a traumatic injury to avian sensory epithelium, supporting cells can replace the dead hair cells either by directly transdifferentiating into hair cells (bottom left), or by re-entering the cell cycle and undergoing asymmetric differentiation, where one daughter cell trans-differentiates into a hair cell and the other remains as a supporting cell.

Figure 2

Hypothesized scheme for how Notch signaling maintains hair cell and supporting cell fates. Hair cells express the hair cell-specific transcription factor Atoh1 and the Notch ligands Delta1 and Jagged2. These signal to neighboring supporting cells through Notch receptors. Cleavage of the Notch receptor releases an intracellular domain (ICD) that travels to the nucleus and co-operates with RBPJk to activate transcription of Notch target genes such as members of the Hes and Hey gene families. These Hes family genes repress expression of hair cell-specific genes such as Atoh1 and maintain the supporting cell state. When Notch signaling is blocked in supporting cells (bottom left), Atoh1 and other hair cell genes are no longer repressed, and supporting cells trans-differentiate into hair cells. In models of Atoh1-based gene therapy (bottom right), the ectopic expression of Atoh1 is hypothesized to drive supporting cells to a hair cell fate.