Stem cell studies in hearing regeneration

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Rows of sensory cells (green) next to accessory cells (red) in the rat inner ear. Credit: John Duc Nguyen and Juan Llamas/Segil Lab

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Rows of sensory cells (green) next to accessory cells (red) in the rat inner ear. Credit: John Duc Nguyen and Juan Llamas/Segil Lab

A deaf adult cannot recover hearing because the sensory hearing cells in the inner ear do not regenerate after damage. In two new studies, published Proceedings of the National Academy of Sciences (PNAS), USC stem cell scientists explain why this is and how it can be reversed.

„In non-sensory accessory cells in the inner ear, key genes needed to transform into sensory cells are turned off through a process called 'epigenetic silencing.’ By studying how genes are turned off, we are beginning to understand how we can turn them back on to restore hearing,” said first author John Doug Nguyen. said. One of the papers.

Second sheet Investigates when and how the ability to form sensory auditory cells is first acquired in the inner ear and describes two specific genes useful in regenerating hearing in adults.

„We focused on the Sox4 and Sox11 genes because we found that they are essential for the formation of sensory auditory cells during development,” said Emily CC Wang, first author of the paper.

One important way genes are turned 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 instructing a cell to become a sensory auditory cell is methylated, the cell cannot access these instructions.

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Through their experiments with non-sensory accessory cells extracted from the inner ears of mice, Nguyen and his colleagues confirmed that DNA methylation silences genes that promote transformation into sensory hearing cells, including the gene Atoh1. Development.

An enzyme called DET removes methyl groups from DNA, reversing gene silencing and restoring the ability of the supporting cells to transform into sensory hair cells. Accordingly, when the scientists blocked the activity of TET, the accessory cells retained their DNA methylation and were therefore unable to transform into sensory hair cells in the Petri dish.

Interestingly, in a separate experiment, the researchers tested the degree of gene silencing that supports cells from a chronically deafened mouse. They found that the gene silencing was partially reversed, meaning that the supporting cells had the ability to respond to signals to transform them into sensory hearing cells.

This finding has important implications: the loss of sensory auditory cells may partially reverse gene silencing that supports cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals may already be naturally converted to sensitized hearing cells.

In a second paper, Wang and his colleagues investigated when and how progenitor cells of the inner ear acquire the ability to form sensory hearing cells.

The scientists pointed out that between days 12 and 13.5 of embryonic development in mice, embryonic cells acquire this ability. During this window, retrograde cells acquire the ability to respond to signals from the master regulator gene Atoh1, which induces the formation of sensory auditory cells during development.

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Two additional genes that alter the status of these cells, Sox4 and Sox11, are also expressed in progenitor cells that respond to Atoh1.

In embryonic mice lacking Sox4 and Sox11, progenitor cells in the inner ear fail to develop into sensory hearing cells. Specifically, loss of Sox4 and Sox11 made the cells’ DNA inaccessible—an effect similar to DNA methylation. Because their DNA is inaccessible, progenitor cells cannot respond to Atoh1’s signals.

On the other hand, high levels of Sox4 and Sox11 activity induce mouse progenitor cells and progenitor cells to form sensory auditory cells in a Petri dish.

Even more promising, in mice with damaged sensory cells in the inner ear, high levels of Sox4 and Sox11 activity increased the percentage of vestibular accessory cells that were converted into sensory receptor cells from 6 percent to 40%.

„We are excited to continue to investigate the mechanisms by which cells in the inner ear acquire the ability to differentiate into sensory cells during development. The paper’s corresponding author is Ksenia Gnedeva, assistant professor in the USC Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, and the Department of Stem Cell Biology and Regenerative Medicine. He is a professor.

More information:
John D. Nguyen et al., DNA methylation in mouse cochlea promotes maturation of accessory cells and contributes to 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 the potential for sensory differentiation in mammary organs of cardia, Proceedings of the National Academy of Sciences (2023) DOI: 10.1073/pnas.2301301120. doi.org/10.1073/pnas.2301301120

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Press Information:
Proceedings of the National Academy of Sciences


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