Regeneration of Inner Ear Hair Cells

Timothy C. Hain, MD • Last revision: May 7, 2022

See also: bilat_causebilat_preventBilat_recentbilat_vngentamicin_toxicityototoxic_dropsototoxins progressive_bilateral regeneration sensory_substitution


Many processes that affect the inner ear kill the main sensory part of the ear, hair cells. While it would seem reasonable that hair cells should be replaced when they are lost, this seems to be species specific. Hair cells of birds, both auditory and vestibular, regenerate but hair cells of humans are generally felt to not regenerate. Fish can also regenerate hair cells (Lush and Piotrowski, 2014). There may be just a little regeneration in the human vestibular system.

On the other hand, in birds, auditory hair cells regenerate rapidly after exposure to ototoxic aminoglycoside antibiotics, and noise. If we could regenerate hair cells in humans, it seems likely that much hearing and balance disease might simply disappear. Imagine - -instead of getting a hearing aid when one is 70 years old, one simply had an injection through the ear drum and restoration of hearing after a few months !

Vestibular hair cells also regenerate in birds, with both the vestibulocollic and vestibuloocular reflexes recovering full functionality after aminoglycoside exposure in chickens (Rubel et al, 1991; Corwin et al, 1991; Goode et al, 1999; Carey et al, 1996; Boyle et al, 2001). It was initially thought that things were very simple and that hair cell regeneration in birds depended on a gene missing from Humans, Math 1. If birds can regenerate their hair cells, it seems reasonable that people might also be able to do this, perhaps with the correct growth factor or genetic trigger. An method that has some experimental support is to transvect the Math 1/atoh1 gene into mammalian (mouse) hair cells. (Staecker, Praetorius et al. 2007; Staecker et al, 2014). Unfortunately, things do not seem quite so simple (see below).


Diensthuber and Stover (2018) discuss strategies for regenerative therapy of hearing loss. They discuss stem cell-based, gene transfer-based, and pharmacological interventions. They say: "Although there is still a long and bumpy road ahead until a true breakthrough is achieved, it seems more realistic than ever that regenerative therapies for the inner ear will find their way into clinical practice."

Although regeneration in birds was first reported in 1988, as of 2016, there are currently no published protocols in mice or other mammals (including humans) that show that there is successful regeneration of hearing. There appear to be many roadblocks in the way (Groves et al, 2013). As an example, although introduction of ATOH1 into guinea pigs can increase the number of cells that express hair cell markers, this is not accompanied by functional improvements in hearing (Atkinson et al, 2014). The hair cells generated are not functional.

Another approach involves manipulating cells expressing a marker protein called LGR4 (leucine-rich repeat-containing G protein coupled receptor 5). Shi and Edge (2013) and McLean et al (2016) discuss potential for stimulating production of new supporting cells in the cochlea using a cocktail of small molecules including various growth factors that modulate signaling pathways, Wnt and Notch. A Connecticut company called "Frequency Therapeutics" (, was founded by the government funded investigators who developed this approach. According to an article in Jama, Edge has "cast his lot" with a Dutch company, Audion Therapeutics (, again planning to exploit this government funded research (Lyon, 2017).

Thus, things do not seem quite so simple that all that is needed is just to move a gene from birds into humans. Rather it appears, that like other systems, there are a multitude of factors involved in hair cell regeneration including the Notch signaling pathway, the ATOH1/Hes signaling cascade, the stem cell marker, Sox1, and unconventional myosin motor proteins (Cotanche and Kaiser, 2010). Ku et al (2014) suggested that there were 212 differentially expressed genes in the regenerative time course, that fall into nine distinct gene expression patterns. Thus it looks as if early ideas about hair cell regeneration were hugely oversimplified.

Another approach to hair cell regeneration is to use stem cells (which can turn into anything), presumably combined with some mechanism to prevent these cells from growing into, lets say, teeth rather than hearing or vestibular sensors (hair cells). Taura et al (2016) reported that stem cells, injected into mice utricle, developed into neuron like cells, possibly neurons. These are not hair cells -- but rather something resembling vestibular ganglion cells located in the wrong portion of the ear. This is a very early effort with no practical implication for the time being. Our guess is that if anything practical comes out of this, it will be in about 25 years. Far more understanding is needed of how stem cells can be programmed.

As of 2018, it appears likely that simple attempts to transvect genes into mammals, including humans, may fail in the short term, and that use of hair cell regeneration to treat hearing loss or vestibular loss may depend on a much more detailed understanding of the cascade of events and genetics involved.