Recent advances in hair cell regeneration research

Abstract

Purpose of review: This review discusses recent progress in research that seeks to understand the regeneration of hair cells and highlights findings that may hold importance for the eventual development of regenerative therapies for hearing and balance impairments.

Recent findings: Signaling via the Notch receptor and the basic helix-loop-helix transcription factors has important roles in the development and regeneration of hair cells. The cytoskeletal properties and cell-matrix interactions of supporting cells in mice of different ages may hold part of the explanation for the age-related differences in their proliferative responses to damage and the differences between mammals and nonmammals in hair cell regeneration. Progress also has been made in deriving stem cells from inner ear tissues and other sources and in the evaluation of their potential uses as sources of new hair cells and as tools for biomedical research.

Summary: Much has been accomplished since the discovery of postembryonic hair cell production and hair cell regeneration in nonmammals decades ago. No therapies for hair cell regeneration are under clinical trials, but research is yielding potentially important discoveries that are likely to lead to the development of therapeutic methods for inducing hair cell regeneration in the mammalian inner ear.

Figure 1. Notch signaling in cell fate determination

Developing hair cells express the ligands Jagged and Delta. Those ligands bind to the Notch receptors of adjacent cells, and that leads to γ-secretase mediated cleavage and generation of a Notch intracellular domain (NICD). After tranlocation to the nucleus, NICD forms a complex with CBF1 and other proteins, and upregulates the expression of Hairy and enhancer of split (HES) and related HEY genes, which block the effects of Atoh1, leading to inhibition of hair cell fate and the development of the cell as a supporting cell. Developing hair cells express Atoh1 which is necessary for hair cell differentiation. Inhibitors of γ-secretases such as DAPT appear to interrupt Notch signaling by blocking the generation of the NICD.

Figure 2. Cell proliferation in mammalian supporting cells (SC) correlates with SC spreading and is influenced by growth factors and cyclin-dependent kinase inhibitors

A. Glial Growth factor (GGF2), Epidermal growth factor (EGF), Transforming growth factor (TGFα), Insulin, Insulin-like Growth Factor and other extracellular signals can promote robust cell production in sensory epithelia from neonatal mammals. On the other hand, the cyclin-dependent kinase inhibitor p27^Kip1 helps to maintain supporting cell in a mitotically quiescent state. When supporting cells change from their normal elongated columnar shape to spread and more flattened shapes their capacity for proliferation is enhanced. B. In mammalian vestibular epithelia, the capacity for cellular spreading and cell proliferation decline during the first week after birth and that appears to contribute to the limited regeneration that is characteristic of mammals.