Taking Hair Cell Regeneration Down a Notch

By Andy Groves

Hearing Restoration Project (HRP) consortium scientists, Andy Groves and Stefan Heller had their research published in Frontiers in Cellular Neuroscience on March 31, 2015. Below is a summary of their research:

Sensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells.

During the development of the inner ear, newly-born hair cells send signals to their neighbors that instruct them to not become hair cells, but to become supporting cells instead. Hair cells are the mechanosensitive cells of the ear. Supporting cells surround them and as their name implies, physically support them and help regulate some of the properties of hair cells. One of these signals is an evolutionarily ancient pathway, the Notch signaling pathway. We and others have shown that if you block the Notch signaling pathway in the cochlea or balance organs of young mice, the supporting cells no longer get the message to stay as supporting cells, and instead they transform into hair cells. This process also happens during hair cell regeneration in birds - supporting cells transform into hair cells, which then send a Notch signal to their neighbors and prevent too many hair cells from being formed.

These observations suggest that it might be possible to block Notch signaling in mature, deafened animals as a means of getting new hair cells to form. We performed a simple experiment to test this in progressively older and older animals. To our surprise, we found that once mice are more than a week old, blocking Notch signaling has no effect on the cochlea any more, and no new hair cells are made.  We showed that this was due in part to components of the Notch signaling pathway being switched off in the ear as the animals get older. Viewed this way, the Notch signaling pathway can be thought of as a “Scaffold” - it is used to allow the cochlea to be built in the first place, but is then dismantled once the cochlea becomes functional.

What does this mean? It suggests that inhibiting Notch signaling alone is unlikely to be an effective means of hair cell regeneration in mammals. It is possible that other factors will be required, and some HRP members are busy testing these other pathways right now. It will also be of great interest to understand HOW the Notch pathway is dismantled with age, whether we can exploit this in future therapies.

Read more about this research proposal here: http://hearinghealthfoundation.org/hrp-consortium-projects-groves-segil-stone.

This work was supported by Department of Defense Grant DODW81XWH-11-2-004(AKG) and Hearing Restoration Project consortium grants from the Hearing Health Foundation (AKG and SH), NIH grant DC004563 (SH), NIH grant P30DC010363 (SH, JSO), and NIHR01DC014450 (JSO).

Hair cell regeneration is a plausible goal for the treatment of hearing and balance disorders. The question is not if we will regenerate hair cells in humans, but when. Your financial support will help to ensure we can continue this vital research and find a cure in our lifetime! Please help us accelerate the pace of hearing and balance research and donate today. Your HELP is OUR hope!

If you have any questions about this research or our progress toward a cure for hearing loss and tinnitus, please contact Hearing Health Foundation at info@hhf.org.

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