Researchers based at the University of Southern California (USC) have unlocked the pathways through which sensory hearing cells in the ear are created and subsequently silenced, which they believe will help develop new treatments for hearing loss in the future.
In two research papers published in PNAS, experiments in mice in one paper revealed how the body blocks other cells converting into sensory hair cells through epigenetic signaling and how this process could be reversed to create new sensory cells.
“In the non-sensory supporting cells of the inner ear, key genes required for conversion to sensory cells are shut off through a process known as ‘epigenetic silencing.’ By studying how the genes are shut off, we begin to understand how we might turn them back on to regenerate hearing,” said John Duc Nguyen, the first author of the first paper, in a press statement. Nguyen now works at Genentech.
The other paper, also carried out in mice, looks at how sensory hearing cells are formed during embryonic development and the genes that help them develop correctly.
“We focused on the genes Sox4 and Sox11 because we found that they are necessary for forming sensory hearing cells during development,” said the paper’s first author Emily Xizi Wang, now based at Atara Biotherapeutics.
In their study, Nguyen and colleagues discovered that the reason it is normally impossible to regenerate sensory hair cells is because the cells that form the sensory cells during embryonic development have accumulated methylation markers on their DNA that prevent them from being able to form new sensory cells.
They found that an enzyme called ten-eleven translocation (TET) can remove methylation from the DNA and restore the ability of supporting cells in the ear to differentiate into sensory hearing cells. Notably in a mouse model of hearing loss, the gene silencing seen in mice with normal hearing seemed to be partially reversed.
Wang and colleagues found that early-stage “progenitor” cells are triggered to develop into sensory hearing cells between 12 and 13.5 days of development in mice. A gene called Atoh1, controls this process.
In order for the progenitor cells to change into sensory cells, active copies of two genes—Sox4 and Sox11—are needed. If these genes are inactive then no sensory cells are formed.
“Understanding the molecular basis of competence acquisition by the lineage-specific progenitor cells provides insights into tissue development and regeneration,” the authors wrote.
“We’re excited to continue exploring the mechanisms by which cells in the inner ear gain the ability to differentiate as sensory cells during development and how these can be used to promote the recovery of sensory hearing cells in the mature inner ear,” added the paper’s lead author Ksenia Gnedeva, PhD, an assistant professor at USC.
This research is at an early stage, and more work needs to be done in humans. However, the researchers hope their findings can inform further investigations assessing whether therapies that switch on sensory hearing cell formation could be developed to treat some types of hearing loss.
