Research on inner ear development sets the stage for reversing hearing loss

By John Murphy, MDLinx
Published January 5, 2016

Key Takeaways

Researchers have taken the first step toward reversing hearing loss in adult humans by learning how the inner ear develops in embryonic mice.

Scientists at Washington University School of Medicine in St. Louis, Mo., used a mouse model to identify two signaling molecules, called fibroblast growth factors (FGFs), which are necessary for the full development of the cochlea. Without both signals, the embryo does not produce enough of the cells that eventually make up the adult cochlea, which results in a shortened cochlear duct and impaired hearing.

“To eventually be able to restore hearing, we would like to be able to regenerate the sensory hair cells of the cochlea,” said senior author David M. Ornitz, MD, PhD, the Alumni Endowed Professor of Developmental Biology. The sensory hair cells of the cochlea pick up sound vibrations and transmit those signals to the brain. Hearing loss occurs when these hair cells are damaged. Humans and other mammals can’t regenerate these cells.

“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,” Dr. Ornitz said. “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.”

In this new study, published online in the journal eLife, Dr. Ornitz and his colleagues showed that proper inner ear development in mice depends on the presence of the signaling molecules FGF9 and FGF20. Normal signaling of these molecules in the inner ear turns on at about day 11 of the mouse embryo’s usual 20-day development. Within the next 2 to 3 days, FGF9 and FGF20 tell the progenitor cells to multiply. By embryonic day 14, the progenitor cells stop multiplying and begin to differentiate to become functional adult sensory cells. At this point, the cellular population that comprises the adult ear is largely complete.

“In mammals, including mice and people, the number of sensory progenitor cells is fixed,” said first author Sung-Ho Huh, PhD, instructor in developmental biology. “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.”

In their study, the researchers found that FGF9 and FGF20 send signals to their receptors, which are located in nearby cells that surround the developing sensory cells. By signaling to these surrounding cells, FGF9 and FGF20 promote the growth of the sensory progenitor cells. This signaling activates a feedback loop that helps to direct the proper development of the cochlea.

The researchers' next step is to identify the molecules involved in the feedback mechanism.

“We have discovered that an FGF signal is instructive in forming the cochlea,” Dr. Ornitz said. “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.”

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