HEAD & NECK SURGERY - Stanford University School of Medicine

S TANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY
R ESEARCH P ROGRAMS
CURING HEARING LOSS
AND UNLOCKING THE SECRETS
OF HOW THE EAR WORKS
Stefan Heller, PhD
All hearing sensation is derived from the
electrical output of a remarkably small
number of sensory cells: fewer that
15,000 per inner ear at birth. These hair
cells are the mechanoelectrical transducers
of the inner ear: deflections of the
sterociliary bundles on their apical surfaces
lead to transmitter release from
their basolateral poles, leading, in turn, to
signal generation in the peripheral axons
of the auditory nerve fibers.
Most types of congenital and acquired
hearing loss arise from damage to, or
loss of, these sensory cells or their associated
neurons. The incidence of heritable
deafness is high: one child in a thousand
is born deaf; another one in a thousand
becomes deaf before adulthood. The
prevalence of acquired hearing loss is rising,
as the population ages, and as noise
pollution steadily increases. It is estimated
that one in three adults over the age
of 65 has a handicapping hearing loss,
and this impairment is largely due to the
irreversible loss of sensory cells.
Underlying the irreversibility of hearing
loss in mammals is the incapacity to
replace lost hair cells by cell division or
by regeneration from endogenous cells
6
The image shows integration and differentiation of inner ear progenitor cells derived
from mouse embryonic stem cells after injection into the chicken’s developing
inner ear (otic vesicle). In (A), some of the injected cells, which are expressing
the ß-Gal marker gene are found to integrate into the epithelium of the otic
vesicle (arrow). Shown in (B) and (C) are embryonic stem cell-derived cells found
3 days after injection (in green). These cells start expressing markers of hair cells,
such as myosin VIIA (red) and appear to have integrated well into the chicken
auditory epithelium where they are surrounded by endogenous chicken hair cells
(non green cells, labeled red). (D) and (E) show that the mouse cells, here visualized
with a blue ß-Gal staining with developed hair bundles that are immunopositive
for the hair bundle marker protein espin.
in the inner ear epithelia. Hair cell
replacement, either by stimulation of
regeneration (as occurs naturally in nonmammalian
vertebrates) or by transplantation
of progenitor cells capable of differentiating
into hair cells, remains
therefore the ultimate goal in the development
of treatment applications to
reconstruct the damaged inner ear.
Our recent work has focused on creating
inner ear cell types, in particular hair cells
and auditory neurons, from a renewable
source.
We have shown that embryonic stem
(ES) cells and adult inner ear stem cells
can serve as such a
source, and we are
currently exploring
signaling pathways
that control hair cell
and neuronal (re-)
generation in vitro
and in vivo.
Our research does
not only focus on
generating inner
ear replacement
parts. We are also
exploring novel
methods to deliver
such replacement
parts into the damaged
cochlea or
whether it is possible
to use drugs to coax
cells of the adult
damaged cochlea
into a prenatal status,
which could result
in self-repair of the damaged mammalian
cochlea.
In an independent line of research, we
are pursuing the structural basis of hair
cell mechanoreception. Although the
individual molecular components of the
mechanoelectrical transduction apparatus
are not known, we and other laboratories
have identified a number of
potential candidates. Our goal is to solve
the atomic structure of the different
components of the transduction machinery
to study the molecular hinges and
mechanisms that
mechanically gate the
elusive ion channel
that is central to our
senses of hearing and
balance.
THE THERAPEUTIC RELEVANCE
OF HAIR CELL BIOPHYSICS
Anthony Ricci, PhD
Hair cells are the sensory cells of the
inner ear. They are responsible for converting
mechanical signals into one recognized
by the brain. Hair cells get their
name from having a tuft of hair-like cilia
at their apical surface. Deflection of these
stereocilia opens mechanically-gated ion
channels that convert the mechanical
signal into an electrical signal. This
process, termed mechanotransduction is
critical to both hearing and balance. Perturbations
of this system are associated
with both temporary and permanent
hearing loss, with age-related and noiseinduced
hearing loss and may even be
associated with tinnitus and vertigo.
Understanding the mechanisms involved
in regulating mechanotransduction may
elucidate new and novel sites for intervention.
Characterizing these pathways
might also lead to new technological
breakthroughs in hearing aid and
cochlear implant development as well as
in the design of novel noise prevention
devices. Over the past several years my
laboratory has identified several important
attributes of mechanotransduction.
First, we have discovered a new process,
called fast adaptation that is critical for
establishing frequency discrimination, or
the ability of the ear to separate sound
into its individual frequency components.
Second, we demonstrated for the
first time, biochemical regulation of
mechanotransduction. This pathway may
provide a new site for pharmacological
intervention in preventing noise-induced
hearing loss. Third, we have recently
demonstrated the importance of
mechanotransduction in controlling the
electrical properties of hair cells. As
mechanotransduction is very sensitive to
its ionic environment, particularly the
concentration of calcium, the importance
of maintaining low levels of calcium
bathing the hair bundle has become
more apparent. Characterizing the regulation
of extracellular calcium may provide
a new pathway for intervention and
may shed light on pathologies related to
loss of ionic homeostasis within the ear.
And finally we are involved in identifying
a mechanism associated with mechanotransduction
and the hair bundle that