New research has taken scientists on the first step to reversing hearing loss in adults, by revealing how the inner ear develops in mice embryos. Researchers at the Washington University School of Medicine in St. Louis, MO have used this mouse model to identify two signaling molecules called fibroblast growth factors (FGFs), which are required for the overall development of the cochlea. Both of these two signalers are necessary for the embryo to produce enough of the cells that grow to make up the adult cochlea. Without full production of these cells, a shortened cochlear duct and impaired hearing results.
The hair cells of the cochlea translate sound vibrations as signals to the brain. When these hair cells are damaged, hearing loss occurs, as humans and other mammals are unable to regenerate these cells.
“To eventually be able to restore hearing, we would like to be able to regenerate the sensory hair cells of the cochlea,” says senior author David M. Ornitz, MD, PhD, the Alumni Endowed Professor of Developmental Biology. “If the inner ear in birds and fish is damaged, cells in the inner ear are naturally turned back into progenitor cells that are capable of replacing the sensory cells. But mammals are more complex, with a better sense of hearing over a wider range of sounds. However, it is thought that in exchange for better hearing, we have lost the ability to regenerate sensory hair cells.”
This new study, published in the online journal eLife, shows that ideal inner ear development in mice depends on the aforementioned signaling molecules, FGF9 and FGF20. Dr. Ornitz and his colleagues found that normal signaling of these molecules in the inner occurs around day 11 of the mouse embryo’s usual 20-day development. During the next 2 to 3 days, FGF9 and FGF20 instruct the progenitor cells to multiply. The progenitor cells cease multiplying and begin to differentiate into functional adult sensory cells around embryonic day 14. At this point, the cellular mélange that makes up the adult ear is mostly complete.
“In mammals, including mice and people, the number of sensory progenitor cells is fixed,” says first author on the paper and instructor in developmental biology, Sung-Ho Huh, PhD. “This number is determined by cell division or cell death in early stages of development. In mice, that’s between about embryonic days 11 and 14. Once that developmental window is closed, the number of cells you have is all you get. There is no compensating for low numbers.”
With this study, the researchers observed that FGF9 and FGF20 send signals to receptors that are located in cells nearby the developing sensory cells. Signaling these surrounding sells allows FGF9 and FGF20 to promote the growth of the sensory progenitor cells. This signaling begins a feedback loop that assists in directing the proper development of the cochlea.
The scientists’ next task is to ascertain the molecules involved in the feedback mechanism.
“We have discovered that an FGF signal is instructive in forming the cochlea,” Dr. Ornitz says. “These FGF signals tell the surrounding tissue to make a factor—we don’t know yet what that factor is, but we know it regulates progenitor cell growth. And being able to grow progenitor cells, or instruct cells that can become progenitor cells to grow, is one key to restoring hearing.”