Adults who have lost their hearing are unable to regain it because damaged inner ear sensory hearing cells do not renew. USC stem cell researchers explain why this is the case and how we might be able to change it in two recent studies that were published in the Proceedings of the National Academy of Sciences (PNAS).
Through a process known as “epigenetic silencing,” critical genes necessary for the conversion of non-sensory supporting cells in the inner ear to sensory cells are turned off. John Duc Nguyen, the first author of one of the publications, explained that by examining how the genes are turned off, we can start to understand how we might switch them back on to regenerate hearing.
The second study investigated when and how sensory hearing cells first develop in the inner ear and described two specific genes that may be helpful for adult hearing regeneration.
According to the paper’s first author Emily Xizi Wang, “We concentrated on the genes Sox4 and Sox11 because we found that they are necessary for the formation of sensory hearing cells during development.”
The subject of Nguyen’s paper, methyl groups are chemical substances that bond to DNA and render it inaccessible, and they play a significant role in the “silencing” or shutting off of genes. A cell cannot access these instructions when the DNA that directs it to become a sensory hearing cell is methylation.
Nguyen and his colleagues tested the hypothesis that DNA methylation silences genes that promote conversion into sensory hearing cells, including the gene Atoh1, which is known to be a master regulator of inner ear development, by using non-sensory supporting cells taken from the inner ears of mice.
By removing methyl groups from the DNA, an enzyme known as TET can undo gene silencing and restore the ability of supporting cells to differentiate into sensory hair cells. Therefore, when the TET pathway was disrupted, the supporting cells maintained their DNA methylation and were unable to differentiate into sensory hair cells in the petri dish.
In an intriguing second experiment, the scientists examined the degree of gene silencing in supporting cells from a mouse model of persistent deafness. They discovered that gene silencing had been partially undone, which meant that the supporting cells could respond to signals and change into sensory hearing cells.
The loss of sensory hearing cells alone may partially undo gene silencing in supporting cells in chronically deaf people, which has significant ramifications. If so, the supporting cells in people with chronic hearing loss may already be predisposed to develop into sensory hearing cells.
In the second publication, Wang and her coworkers investigated when and how the inner ear’s progenitor cells acquire the capacity to develop sensory hearing cells.
In mice, progenitor cells gain this capacity between days 12 and 13.5 of embryonic development, according to the researchers. The progenitor cells develop the ability to react to signals from the master regulator gene Atoh1, which later in development causes the production of sensory hearing cells.
Two more genes, Sox4 and Sox11, which alter the status of these cells, are what prepare the progenitor cells to react to Atoh1.
Progenitor cells in the inner ear that lack Sox4 and Sox11 do not differentiate into sensory hearing cells in developing mice. Particularly, loss of Sox4 and Sox11 resulted in the cells’ DNA being inaccessible, a phenomenon akin to DNA methylation. The progenitor cells were unable to respond to signals from Atoh1 because their DNA was unavailable.
However, in a petri dish, Sox4 and Sox11 activity at high levels induced mouse progenitor cells and supporting cells to differentiate into sensory hearing cells.
Even more encouragingly, high levels of Sox4 and Sox11 activity enhanced the proportion of vestibular supporting cells that differentiated into sensory receptor cells—from 6 percent to 40%—in mice with damaged sensory cells in the inner ear.
The paper’s corresponding author, Ksenia Gnedeva, an assistant professor in the USC Tina and Rick Caruso Department of Otolaryngology—Head and Neck Surgery and the Department of Stem Cell Biology and Regenera, said, “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.”
More information: John D. Nguyen et al, DNA methylation in the mouse cochlea promotes maturation of supporting cells and contributes to the failure of hair cell regeneration, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2300839120
Wang, Xizi et al, SoxC transcription factors shape the epigenetic landscape to establish competence for sensory differentiation in the mammalian organ of Corti, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2301301120. doi.org/10.1073/pnas.2301301120
