Mouse studies tune into hearing regeneration

 A deafened adult cannot recover the ability to hear, because the sensory hearing cells of the inner ear don't regenerate after damage. In two new studies, partially funded by the National Institutes of Health and published in the Proceedings of the National Academy of the Sciences (PNAS), USC Stem Cell scientists explain why this is the case and how we might be able to change it.

"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 one of the papers. Nguyen now works at the biotech company Genentech and earned his PhD in the USC Stem Cell laboratory of Neil Segil, who passed away from pancreatic cancer in 2022.

The second paper explored when and how the ability to form sensory hearing cells is gained in the inner ear in the first place and describes two specific genes that could be useful for regenerating hearing in adults.

"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, who also conducted her research as a PhD student in the Segil Lab and works at the biotech company Atara Biotherapeutics.

Gage Crump, a co-author on both papers and the interim chair of USC's Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, added: "These two papers are not only great science, but also a clear example of Neil Segil's enduring legacy as an exceptional mentor to the next generation of stem cell researchers."

Silencing isn't golden

One important way that genes are shut off or "silenced" involves chemical compounds called methyl groups that bind to DNA and make it inaccessible -- the focus of Nguyen's paper. When the DNA that instructs a cell to become a sensory hearing cell is methylated, the cell cannot access these instructions.

Through their experiments with non-sensory supporting cells extracted from the inner ears of mice, Nguyen and his colleagues confirmed that DNA methylation silences genes that promote conversion into sensory hearing cells, including the gene Atoh1 that is known to be a master regulator of inner ear development.

An enzyme called TET can remove methyl groups from the DNA, thus reversing the gene silencing and restoring the capacity of supporting cells to convert into sensory hair cells. Accordingly, when the scientists blocked the activity of TET, the supporting cells retained their DNA methylation and therefore could not convert into sensory hair cells in the Petri dish.

Intriguingly, in a separate experiment,, the researchers tested the extent of gene silencing in supporting cells from a chronically deafened mouse. They found that gene silencing was partially reversed, meaning that the supporting cells had the capacity to respond to signals to transform into sensory hearing cells. This finding has important implications: the loss of sensory hearing cells itself might partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals might already be naturally primed to convert into sensory hearing cells., the researchers tested the extent of gene silencing in supporting cells from a chronically deafened mouse. They found that gene silencing was partially reversed, meaning that the supporting cells had the capacity to respond to signals to transform into sensory hearing cells. This finding has important implications: the loss of sensory hearing cells itself might partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals might already be naturally primed to convert into sensory hearing cells., the researchers tested the extent of gene silencing in supporting cells from a chronically deafened mouse. They found that gene silencing was partially reversed, meaning that the supporting cells had the capacity to respond to signals to transform into sensory hearing cells. This finding has important implications: the loss of sensory hearing cells itself might partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals might already be naturally primed to convert into sensory hearing cells.