Inner Ear Development | Angelika Doetzlhofer, Ph.D

My name is Angelica Thetzlwolfo, and I’m one of
the two new faculties that have been recruited to this
Center for Sensory Methodology.>>I have my primary appointment
in the Department of Neuroscience, but by heart I’m
a developmental biologist. So my laboratory studies how
the auditory sensory epithelium develops. In particular, we are interested
in how this beautiful array of mechanosensory hair cells is
established during development. I don’t know if you saw some of
the images, but in the mammalian in our cochlear,
hair cells are arranged in rows. So we have two different types
of mechanosensory hair cells, inner and outer hair cells, and we have a single row of
inner hair cells and free rows of outer hair cells
that stretched all the way, all the length of the cochlear
coil, and this is quite remarkable to have such
a precise arrangement of cells. And such arrangement really
demands a mechanism that ensure the right number of cells are
produced at the right time and at the right place, and so
over the last several years, my laboratory was studying some
of the molecular mechanisms that are engaged in ensuring that
these processes occur properly. We found, for example, that
a signaling pathway that allows cells to communicate with each
other, which we refer to as notch signaling ensures that the
right ratio of hair cells and supporting cells are produced. So, if you disrupt this pathway, you over produce these
mechanosensory hair cells, and what happens is actually these
cells will degenerate without the support of
the supporting cells. Meaning that it is
really critical to get the fine balance of getting
the number of cells right. More recently, we also looked
into the question of how can you ensure that these cells
are produced at the right time at the right place, and
we found that a highly conserved signaling pathway, which
consists of microproteins and RNA binding proteins,
the [INAUDIBLE] instructs cells to stop dividing and start differentiating at the
right time, at the right place. So you could now ask a question,
Why do we care about how the auditory sensory
epithelium develops? And I would say as
a basic scientist, that it’s a fantastically
beautiful question to ask. Just because we want
to know things, we want to explore things. But, of course,
I’m proud of the medical school. And there’s another really
important reason, and that’s human health. You might know, or you might not
know, but mechanosensory hair cells are only produced
once in our lifetime. And we only have a limited
number of these hair cells, so in our inner ear cochlea we have
about 10,000 hair cells, and if hair cells are lost
due to damage, that could be loud sound, or
to toxic drugs, or even aging, they’re lost
forever, and that really causes functional deficits and
could cause deafness. So, we think that learning
about development might help us in developing strategies for regenerating these cells,
and we think that because, when you look at systems that
do regenerate, very often, they hijack developmental processes,
so they kind of recapitulate, the same process they would
under go during development. We also think that
in particular, the auditory sensory epithelium Introducing cells from
the outside might be hopeless. The auditory sensory perfume
is encapusled in bone, so you can not really use,
induce [INAUDIBLE] stem cells, ES cells and
graph them into the tissue. We have to kind of reprogram
existing cells, and my lab and many other labs are focusing
on a particular cell type, the supporting cells. The supporting cells, really,
surround the air cells, and they share a very close
lineage relationship with these air cells
during development. They derive from a common
pool of progenitors, and as I told you,
pathways like notch signaling partition that pore into hair
cells and supporting cells. And people now look
into manipulating these exact pathways to maybe
force supporting cells to transdifferentiate into hair
cells in the mature tissue. Another reason why people are
really excited about supporting cells is that in species
that do regenerate, these are the exact cell types
that produce hair cells. So birds for example, have a very sophisticated
ability to hear detect sound. Their auditory sensory
epithelium develops quite similarly to ours, but
in contrast to humans, they do regenerate
these hair cells. And the supporting cells
are actually getting reactivated after damage to these cells and
can function as progenitors. And more recently, and
that was part of my study as post doctoral fellow,
we found that even in mammals, in our case we use the mouse as
a model system, the supporting cells have some intrinsic
capacity to produce hair cells. So, when you take them out
of their normal environment, put them in a culture dish, they
can become like progenitors. They start to divide again, and they can differentiate
into hair cells. Meaning that maybe there
are only a couple of factors that limit their ability to
regenerate hair cells, and we think that by studying
fundamental development, we will get a toolbox that can
be applied to maybe forcing these supportive cells into
becoming hair cells, and we hope that future studies will maybe
translate into Therapeutics. Thank you.

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