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What Will It Take to Seal the Deal? Report by Andy Groves, P H D . Hearing Health Magazine,
Winter 2014 Edition. Hearing Restoration Project scientists have identified mammalian inner
ear hair cells that take the first steps toward regeneration and then mysteriously stop. Here
is how they will figure out why. This is the fifth article in a series about current projects
under way in the Hearing Restoration Project. This piece explains Transcriptional profiling
of purified supporting cells from control and damaged adult mouse utricles, with and
without inactivation of Notch signaling, the project of HRP consortium members Andy Groves,
P h d, Baylor College of Medicine. Neil Segil, P h D, University of Southern California.
and Jennifer Stone, P h D., University of Washington. We sincerely thank Dr. Groves
for contributing this story to the magazine. In previous Hearing Health articles in this
series about the Hearing Restoration Project H R P , we have discussed the problem of hair
cell regeneration that in mammals, hair cells, the highly sensitive sound detectors of the
inner ear, are unable to grow back after damage to the ear. As a result, hearing loss in humans
is progressive and permanent. However, although humans and other mammals cannot replace their
lost hair cells, this is not true for other vertebrates. It has been known for more than
25 years that birds, frogs, and fish can regenerate their hair cells naturally. A bird that has
been deafened is able to grow back almost its entire complement of hair cells and hear
again almost perfectly in a matter of weeks. However, mammals apparently lost the ability
to regenerate hair cells at some point over the past 300 million years. How are birds
able to regenerate their hair cells? Every bird hair cell is surrounded by four to eight
supporting cells to form a repeating mosaic pattern. The death of a bird hair cell somehow
triggers one of its neighboring supporting cells to divide to give two daughter cells.
One of the daughter cells then turns into a hair cell, and this process of division
followed by transformation into a hair cell restores the normal mosaic of hair cells and
supporting cells. Regeneration of this type happens normally in some parts of our bodies;
for example, we lose and replace about 10 billion cells every day from the lining of
our digestive system. However, although humans and other mammals also have supporting cells
surrounding their hair cells, there is almost no regeneration of hair cells after damage
in our inner ears. Some of the HRP-supported research has focused on the cochleae of newborn
mice, which have a capacity for hair cell regeneration, albeit a rather limited one
that disappears before mice start to hear at about 14 days after birth. Some HRP consortium
scientists are trying to understand the genetic changes that occur in the cochlea during this
very brief time period. More recently, the lab of HRP member Jennifer Stone, P H D, at
the University of Washington, has made an exciting discovery in another part of the
inner ear called the utricle. The utricle also contains hair cells like the cochlea,
but it uses them to detect gravity rather than sound.
Dr. Stone and her colleagues have pioneered the technique of isolating the utricle from
an adult mouse and growing it in a dish in the lab. Since the adult cochlea is too delicate
to isolate and grow in a dish, this technique is the only one that allows experimental access
to hair cells and supporting cells in adult mammals. The lab found that within a few days
after hair cells are killed in the utricle, the surrounding supporting cells take the
very first genetic steps to activate the program to make hair cells—but then they stop before
the hair cells actually form. It is as though the supporting cells have received a signal
to regenerate new hair cells, but they cannot "seal the deal" and complete the regeneration
program. This situation is very different from the cochlea, where absolutely no hair
cell regeneration steps occur in adults. Can we therefore use the utricle to learn more
about the signals that drive regeneration? In an attempt to identify factors that can
push supporting cells over this roadblock, Dr.
Stone turned to drug inhibitors of the Notch signaling pathway. In our report What Stops
the Inner Ear From Regenerating? in the Fall 2013 issue of Hearing Health, available w
w w . at h h f.org , we discussed how Notch signaling is an evolutionarily ancient form
of cell communication that is frequently used to create mosaic patterns of different cell
types, such as the mosaic repeating pattern of hair cells and supporting cells in the
inner ear. In this scheme, supporting cells make a protein on their cell surfaces. This
is the Notch receptor. Hair cells make proteins on their cell surfaces that bind to the Notch
receptor, like a key fitting into a lock. Binding to the Notch receptor is believed
to actively block supporting cells from turning into hair cells. Dr. Stone and her team found
that if they killed hair cells in the utricle, but then used drugs to block Notch signaling,
they saw small but significant numbers of true hair cells appearing in their experiments.
These results suggest that the Notch pathway may be one of the signals that holds regeneration
back in the adult mammal. Neil Segil, P h D, and I have teamed up with Dr. Stone and
her lab to identify other players that may block regeneration in the utricle. Using Dr.
Stone's culture system, our three labs will use next generation DNA sequencing technology
to identify genes that are switched on in supporting cells of the utricle as they attempt
to transform themselves into hair cells after damage but ultimately fail. We will then see
what genes are switched on or off when drugs that block the Notch pathway are used to finally
complete the process and drive supporting cells to produce hair cells. These experiments
are still at a very early stage, but we hope this approach will complement other work by
members of the HRP consortium that are looking at similar processes in the cochlea.