The Regenerators

A molecular signature makes it possible to trace the details of hair cell replacement in the mammalian inner ear.

Sep 1, 2015
Amanda B. Keener

EDITOR'S CHOICE IN CELL & MOLECULAR BIOLOGY

TRANSFORMERS: Upon damage to hair cells (blue) in a mouse utricle, supporting cells (green) divide and differentiate into hair-cell replacements (red).TIAN WANGThe paper
T. Wang et al., “Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle,” Nat Commun, 6:6613, 2015.

Regeneration
In mammals, hair cells of the utricle (the inner ear organ that senses gravity and maintains balance) can regenerate to some extent after damage, unlike hair cells in the cochlea. Despite evidence in neonatal mice that hair cells’ neighbors, called supporting cells, can differentiate into hair cells, tracking the origins of new hair cells could not be done until Alan Cheng of Stanford University and his team developed a genetic marker based on a gene, Lgr5, that responds to hair cell damage.

Damage control
The researchers found that Lgr5 expression in supporting cells of excised neonatal mouse utricles increased after chemical damage, and, using live-cell imaging, they followed the transformation of individual supporting cells into hair cells. In vivo, lineage tracing showed that numerous hair cells restored after damage retained a fluorescent mark of Lgr5 activation, indicating they had been derived from supporting cells.

Doubling up
Lgr5-expressing cells proliferated in vivo, suggesting they can also replenish hair cell populations by undergoing mitosis before transdifferentiation. Cheng says the ability to both regenerate hair cells and restore their numbers is a sort of “holy grail” for researchers aiming to translate what they know about utricle hair cell regeneration to the hair cells of the cochlea to treat hearing loss.

Molecular clues
“This really gives us a clue into . . . the molecular signatures that we need to focus on to help us promote regeneration in mature animals,” says Jennifer Stone, who studies hair-cell regeneration at the University of Washington in Seattle. Cheng says it’s not clear whether adult mice also express Lgr5, but he plans to find out whether inducing the gene’s expression can restore utricle function.