Rows of sensory hearing cells (green) next to supporting cells (red) in the inner ear of a mouse. Credit: John Duc Nguyen and Juan Llamas/Segil Lab
An adult who ends up being deaf can not regain their hearing given that the inner ears sensory cells, once damaged, dont regrow. In recent research, with partial funding from the National Institutes of Health and published in the Proceedings of the National Academy of the Sciences (PNAS), USC Stem Cell scientists delve into the reasons behind this and explore prospective services.
” In the non-sensory supporting cells of the inner ear, crucial genes required for conversion to sensory cells are shut off through a process referred to as epigenetic silencing. By studying how the genes are shut off, we begin to comprehend how we may turn them back on to restore hearing,” stated John Duc Nguyen, the first author of one of the documents. Nguyen now operates at the biotech company Genentech and made his Ph.D. in the USC Stem Cell lab of Neil Segil, who died from pancreatic cancer in 2022.
The 2nd paper explored when and how the capability to form sensory hearing cells is gotten in the inner ear in the very first location and explains two specific genes that could be beneficial for regenerating hearing in grownups.
” We concentrated on the genes Sox4 and Sox11 due to the fact that we found that they are necessary for forming sensory hearing cells throughout development,” said the papers first author Emily Xizi Wang, who also conducted her research as a PhD student in the Segil Lab and operates at the biotech company Atara Biotherapeutics.
Gage Crump, a co-author on both documents and the interim chair of USCs Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, included: “These two papers are not only fantastic science, but also a clear example of Neil Segils withstanding legacy as an extraordinary coach to the next generation of stem cell researchers.”
Silencing isnt golden
One essential method that genes are shut down or “silenced” includes chemical substances called methyl groups that bind to DNA and make it unattainable– the focus of Nguyens paper. When the DNA that instructs a cell to become a sensory hearing cell is methylated, the cell can not access these guidelines.
Through their try outs non-sensory supporting cells drawn out from the inner ears of mice, Nguyen and his associates verified 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 advancement.
An enzyme called TET can remove methyl groups from the DNA, thus reversing the gene silencing and bring back the capacity of supporting cells to convert into sensory hair cells. Accordingly, when the researchers blocked the activity of TET, the supporting cells maintained their DNA methylation and for that reason might not convert into sensory hair cells in the Petri dish.
Intriguingly, in a separate experiment, the scientists evaluated the extent of gene silencing in supporting cells from a chronically deafened mouse. They discovered 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 may partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf people may already be naturally primed to transform into sensory hearing cells.
Segils longtime partner Andrew K. Groves from the Baylor College of Medicine acted as the papers corresponding author.
Knocking their Sox off
In the 2nd paper, Wang and her associates checked out when and how the progenitor cells of the inner ear gain the capability to form sensory hearing cells.
The scientists pinpointed when progenitor cells obtain this ability: in between days 12 and 13.5 of embryonic development in mice. Throughout this window, the progenitor cells obtain the capacity to respond to signals from the master regulator gene Atoh1 that activates the development of sensory hearing cells later throughout development.
What primes the progenitor cells to react to Atoh1 are two extra genes, Sox4 and Sox11, that change the state of these cells.
In embryonic mice lacking Sox4 and Sox11, progenitor cells in the inner ear stopped working to develop into sensory hearing cells. Particularly, a loss of Sox4 and Sox11 made the cells DNA inaccessible– an impact similar to DNA methylation. With their DNA inaccessible, the progenitor cells couldnt react to signals from Atoh1.
On the flip side, high levels of Sox4 and Sox11 activity promoted mouse progenitor cells and supporting cells to form sensory hearing cells in a Petri dish.
More appealing still, in mice with harmed sensory cells in the inner ear, high levels of Sox4 and Sox11 activity increased the percentage of vestibular supporting cells that converted into sensory receptor cells– from 6 percent to 40 percent.
” Were excited to continue exploring the mechanisms by which cells in the inner ear gain the capability to separate as sensory cells during advancement and how these can be used to promote the healing of sensory hearing cells in the fully grown inner ear,” said the papers matching author Ksenia Gnedeva, who completed her postdoctoral training in the Segil Lab and is now an assistant teacher in the USC Tina and Rick Caruso Department of Otolaryngology– Head and Neck Surgery, and the Department of Stem Cell Biology and Regenerative Medicine.
Referrals: “DNA methylation in the mouse cochlea promotes maturation of supporting cells and adds to the failure of hair cell regrowth” by John D. Nguyen, Juan Llamas, Tuo Shi and Neil Segil, 7 August 2023, Proceedings of the National Academy.DOI: 10.1073/ pnas.2300839120.
” SoxC transcription factors shape the epigenetic landscape to establish proficiency for sensory differentiation in the mammalian organ of Corti” by Wang et al., August 2023, Proceedings of the National Academy of Sciences.DOI: 10.1073/ pnas.2301301120.
Juan Llamas from the Segil lab and Tuo Shi from the Crump lab are co-authors of both research studies. For Wang and Gnedevas paper, extra co-authors consist of Talon Trecek, Litao Tao, and Welly Makmura from the Segil laboratory.
Both studies were supported by the National Institutes of Health (NIH grant RO1 DC015829), in addition to a Hearing Restoration ProjectConsortium award from the Hearing Health Foundation. Nguyen and Groves study received support from three additional NIH grants (F31 DC018703, T32 HD060549, and RO1 DC014832), and Wang and Gnedevas research study received assistance from two additional NIH grants (R21 DC016984 and T32DC009975).
Nguyen now works at the biotech company Genentech and earned his Ph.D. in the USC Stem Cell lab of Neil Segil, who passed away from pancreatic cancer in 2022.
Intriguingly, in a separate experiment, the researchers checked the level of gene silencing in supporting cells from a chronically deafened mouse. This finding has crucial ramifications: the loss of sensory hearing cells itself may partly reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf people might currently be naturally primed to transform into sensory hearing cells.
In embryonic mice lacking Sox4 and Sox11, progenitor cells in the inner ear failed to develop into sensory hearing cells.