Apr. 8, 1999 Damage to the sensory hair cells in the inner ear is the most frequent cause of permanent hearing loss. Such destruction can be due to a number of causes, most notably exposure to loud noise, as well as certain drugs, disease, genetic factors and the natural process of aging.
While birds have the remarkable natural ability to regenerate sensory hair cells, thus restoring their hearing, mammals -- including humans -- unfortunately lack this ability. Dr. Edwin Rubel, professor of hearing science at the University of Washington's Virginia Merrill Bloedel Hearing Research Center, was one of the discoverers of this ability in birds a decade ago.
Now, Rubel and colleagues in Germany, the United Kingdom and Seattle have published results of their latest research in the March 30 issue of the Proceedings of the National Academy of Sciences, providing an explanation for the inability of mammals past the embryo stage to regenerate sensory hair cells. The new research uses mice specially bred without an enzyme that inhibits cell division.
Hair cell production requires the successful completion of two relatively independent processes, explained Rubel. The first set of events (on which the current research focuses) is the division and proliferation of the "support cells" that survive the damage inflicted by loud noise or other causes. Support cells are located in the sensory epithelium (an area called the organ of Corti on the surface of the inner ear) and they surround the hair cells. In birds, these support cells have the ability to divide and proliferate into new support cells and -- in the second step -- into new hair cells.
However, the support cells in the sensory epithelium of the postnatal mammal are terminally differentiated, or incapable of dividing and proliferating, as they are able to do at the embryo stage.
Earlier research showed that such terminally differentiated cells express high levels of enzymes known as cell-cycle inhibitors, in particular cyclin-dependent kinase inhibitors. These inhibitors are thought to prevent the cells that survive damage from noise or other causes from re-entering the cell cycle and dividing and proliferating.
In the current research, Rubel and colleagues show that a particular kinase inhibitor, p27Kip1, is expressed in the supporting cells of the organ of Corti.
In examining mice bred to lack the gene that causes the cells to produce P27Kip1, the researchers found that supporting cells proliferated, as they do in birds. Without the enzyme, the cells are free to divide.
"It is not news that P27 inhibits cell proliferation," said Rubel. "It is important because of its relation to the future for treating hearing loss. We show for the first time that, under some conditions, the support cells in the mammalian organ of Corti can proliferate in the postnatal animal.
"Our results bring us one small but significant step closer to achieving hair-cell regeneration in humans," said Rubel.
"It remains to be determined whether release from such inhibition not only will cause cell proliferation in the organ of Corti, but also initiate further steps required for hair-cell differentiation, maturation, and functional recovery to complete the hair-cell regeneration process," state the authors.
Co-authors are Hubert Lowenheim, David N. Furness, Jonathan Kil, Christoph Zinn, Karina Gultig, Matthew L. Fero, Deanna Frost, Anthony W. Gummer, James M. Roberts, Carole M. Hackney and Hans-Peter Zenner.
The research was supported by grants from the Deutsche Forschungsgemein-schaft, the Wellcome Trust, the National Institutes of Health and the Oberkotter Foundation.
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