Master Genetic Switch Produces Distinct Hair Cells in the Ear

The discovery of a genetic switch could be instrumental in producing mechanosensory hair cells of the inner ear that die due to aging, loud noises, chemotherapy, or antibiotics, resulting in deafness.

A new study in mice has discovered that the gene Tbx2 is a master regulatory switch that triggers the differentiation of inner hair cells (IHCs) versus outer hair cells (OHCs) in the cochlear canals of the inner ear. Aging and loud noises primarily cause OHCs to die, resulting in hearing loss. Until now it was not possible to reprogram existing cells to develop into IHCs or OHCs.

The findings, published in the journal Nature, (“Tbx2 is a master regulator of inner versus outer hair cell differentiation”), overcome a major hurdle that prevented the development of IHCs and OHCs to restore hearing.

“Our finding gives the first clear cell switch to make one type versus the other,” said Jaime Garcia-Anoveros, PhD, a professor of anesthesia, neurology, and neuroscience at Northwestern University Feinberg School of Medicine and lead author of this study. “It will provide a previously unavailable tool to make an inner or outer hair cell.”

Currently, in an experimental stage, the study would enable the reprogramming of supporting cells, latticed among hair cells in the inner ear, to become outer or inner hair cells. “We can now figure out how to make specifically inner or outer hair cells and identify why the latter are more prone to dying and cause deafness,” Garcia-Anoveros said.

The U.S. Centers for Disease Control (CDC) reports half of all individuals 75 years and older and a quarter of all individuals between 65 and 74 have disabling hearing loss in the United States. Researchers in the field of regenerative medicine can produce an artificial hair cell, but this does not differentiate into IHCs or OHCs needed for hearing.

OHCs develop in the embryo and do not multiply. Three rows of OHCs selectively amplify auditory inputs and a single row of IHCs transmits auditory signals to the brain. OHCs inflate and deflate in response to the pressure of sound waves and amplify incoming sound waves for the IHCs to transmit.

“It’s like a ballet. The outers crouch and jump and lift the inners further into the ear,” Garcia-Anoveros said. “The ear is a beautiful organ. There is no other organ in a mammal where the cells are positioned with micrometric precision. Otherwise, hearing doesn’t occur.”

Earlier studies have implicated two genes in the specific differentiation of OHCs but no gene has yet been identified that triggers IHC differentiation. A transcription factor called INSM1 acts in the embryo to establish an OHC fate and prevent OHCs from turning into IHCs. When INSM1 is absent, embryonic OHCs mis-express genes that specify IHCs.

In the current study, the researchers showed that removing Tbx2 from embryonic IHCs results in their expressing early OHC genes such as INSM1 and becoming mature OHCs instead of IHCs. When both INSM1 and Tbx2 are absent in the embryo, only OHCs are produced, indicating Tbx2 is necessary for the abnormal change of OHCs lacking INSM1 into IHCs.

In addition, removing Tbx2 from IHCs after birth turns them into mature OHCs. The authors also showed that abnormal expression of Tbx2 in OHCs changes them into IHCs, indicating Tbx2 is needed and adequate to bifurcate the lineage decision between IHCs and OHCs and maintain the difference throughout development. Overall, Tbx2 expression causes the cell to become an IHC and its absence the cell becomes an OHC.

The ability to specifically produce an IHC or OHC will require a gene cocktail, Garcia-Anoveros said. The ATOH1 and GF1 genes are needed to make a cochlear hair cell from a non-hair cell. Then TBX2 must be turned on or off to produce the needed inner or outer cell, respectively.