Towards the Regrowth of Lost Sensory Hair Cells in the Inner Ear
Age-related deafness arises from some combination of (a) the loss of sensory hair cells in the inner ear, and (b) the loss of connections between those cells and the brain. There is some disagreement in the literature as to which of these mechanisms is the most relevant, but most recent efforts in the field are focused on trying to coerce the body into producing new hair cells. If that production of new hair cells in the inner ear follows the normal developmental processes, then it might solve both of the above mentioned issues, providing both cells and connections to the brain.
Today's research materials illustrate the state of this field of research. The scientists involved have explored the developmental programs active in the inner ear tissue of the embryo in search of regulatory genes that might be used to reactivate the normally dormant production of new hair cells in an adult. Interestingly, they also find that loss of hair cells in an adult can trigger these developmental programs to a modest degree, producing some amount of new hair cell creation - though evidently not enough. Yet if a process operates at all in adult tissues, one might think that it will be an easier target for upregulation via the usual therapeutic strategies than would otherwise be the case.
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 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, researchers can begin to understand how we might turn them back on to regenerate hearing.
Researchers explored when and how the progenitor cells of the inner ear gain the ability to form sensory hearing cells. The scientists pinpointed when progenitor cells acquire this ability: between days 12 and 13.5 of embryonic development in mice. During this window, the progenitor cells acquire the capacity to respond to signals from the master regulator gene Atoh1 that triggers the formation of sensory hearing cells later during development. What primes the progenitor cells to respond to Atoh1 are two additional genes, Sox4 and Sox11, that change the state of these cells.
In adult mice with damaged 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. "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."
One important way that genes are shut off or "silenced" involves chemical compounds called methyl groups that bind to DNA and make it inaccessible. When the DNA that instructs a cell to become a sensory hearing cell is methylated, the cell cannot access these instructions. 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.
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.
Understanding the molecular basis of competence acquisition by the lineage-specific progenitor cells provides insights into tissue development and regeneration. The sensory epithelium of the inner ear represents a convenient model to study this process, as only two cell types - the mechanosensory hair cells and their associated supporting cells - are specified from a single pool of progenitors in this lineage. In the present manuscript, we uncover some of the mechanisms by which competence for mechanosensory receptor differentiation is acquired in the early organ of Corti progenitor cells. Specifically, we show that the two SoxC family members, Sox 4 and Sox11, establish a permissive chromatin landscape that allows the hair cell gene regulatory network to be activated upon differentiation cues.
Age-related hearing loss can significantly impact quality of life. One potential approach to restore hearing is to regenerate mechanosensory hair cells responsible for detecting sound by the conversion of neighboring supporting cells into new hair cells. However, mammalian supporting cells can only transdifferentiate during embryonic and early postnatal development, and this ability is lost before the onset of hearing. We show that supporting cells accumulate DNA methylation, a form of epigenetic silencing, to permanently shut off the hair cell gene program required for successful transdifferentiation. Blocking ten-eleven translocation (TET) enzyme activity extends the window in which transdifferentiation can occur. Moreover, the loss of hair cells by deafening partially reverses DNA methylation in supporting cells, suggesting one avenue for therapeutic intervention.