| HHIssues@aol.com 2005-07-09, 12:12 pm |
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source: bhNEWS
Report by Cheryl Heppner
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12th Annual Research Symposium - July 3, 2005
The Origins of Regenerated Hair Cells
Dr. Jeffrey T. Corwin
Department of Neuroscience, university of Virginia
- The number of hair cells in both the inner and outer ear declines as
we age.
- Early research on fruit flies led to further research. In the 1970s
Dr. Corwin was in the Central Pacific -- Enewetak Atoll -- studying how
sharks could hear and locate sounds. In 1974 he found that a juvenile
shark had 20,000 hair cells but a mature adult had 240,000 hair cells.
In humans, nerve deafness is permanent and we don't regenerate hair
cells.
- Sharks, bony fish and amphibians get new hair cells from cells that
are regenerated when supporting cells divide.
- Doug Cotanche at the university of Hawaii did key research on hair
cell regeneration. He was studying birds for technical reasons, and it
was accidental that he exposed birds to loud sounds, then got them to
sit for 10 days. He found that one preserved its cells immediately, and
that stimulated interest. The newly regenerated hair and support cells
contained new DNA.
- A laser was used to focus inside a hair cell nucleus, and a pulse was
given to shoot and kill them. Time lapse photography showed that
support cells nearby divided and reproduced.
- In non-mammals, hair cell regeneration goes in stages. The support
cells lose their specialty, divide and become two cells. The offspring
can specialize as either a supporting cell or hair cell. The default
fate is to become a hair cell unless the cell is inhibited from
adapting that fate. Replacement hair cells form synapses and restore
hearing and balance function.
- One graduate student liked to tell others that if they were at a rock
concert, and stood next to a speaker for a certain amount of time with
a chicken, the chicken's hair cells would grow back in 10 days but
human hearing loss would be
permanent. We're trying to become more like chickens.
- Can mammals regenerate hair cells? Tissue from a 52-year-old patient
that would normally be discarded was brought back to the lab. They
wanted to see if it had the machinery to regenerate. The result was
encouraging. Replicated DNA showed new cells could form in hair cell
organs in mature human ears.
- It showed the machinery can occur in older mammals, with hundreds of
cells in a human. But in a bird you would have seen tens of thousands
of hair cells.
- The question then becomes: Can we enhance the occurrence of cell
divisions in mammal ears through supporting cells and wake up the
regeneration machinery in the ear? Or as some scientists like to say,
"a way to step on the gas pedal."
- In tissue culture we can now strongly enhance the proliferation of
supporting cells in the mammalian ear with two drugs --forskolin and a
biotech drug rhGGF2.
- So what are the limits of regeneration? One is the age of the animal.
In examining tissue of a newborn, during the first couple of weeks of
life,
supporting cells were found to be becoming quiescent.
- Microsurgical cuts were made, and these excision wounds healed
rapidly in ears from embryonic mammals.
- Persistent hearing and balance losses are all too common and result
in the loss of one type of cell. That just one type of cell is
responsible is very important to pharmaceutical and biotech companies.
Whether it is a bird or fish, all lose hearing for the same reason.
- Animal models for damage that results in hearing and balance loss are
truly representative of humans.
- Supporting cells are the source of the cells that specialize as hair
replacement cells.
- What is reasonable to expect from research in regeneration? We could
get a major breakthrough at any time. Often breakthroughs are just an
accident when scientists are looking for something else. Research is
moving faster and
faster. Most people in research are optimists.
- Steps needed for hair cell regeneration:
1=2E Induce cell production
2=2E Suspend quiescence
3=2E Induce differentiation (specialization of new cells as replacement
hair cells)
Q: Why did mammals lose the ability to regenerate hair cells?
A: There's no clear reason why it would be an advantage to lose hair
cells. What's unique about our hair cells is that they have a
single-file line, very structured. At no place else in the body do
cells line up in such order. We don't know any reason why evolution
would have caused that.
Q: We don't have a Nancy Reagan to support this research, and the deaf
community opposes it. What should be done?
A: It's completely different for people born deaf than those who
develop hearing and lose it. That point needs to get across. We now
have only about 1/3 of the funding needed for this level of research
and the proposed federal budget cuts this amount. Only about 2/3 of the
work underway will continue to be funded if that amount is not
increased.
Applications for Stem Cells in Restoring Hearing Loss
Dr. Stefan Heller
Massachusetts Eye and Ear Infirmary
Harvard Medical School
- You don't hear with the hair cells, you hear with the brain. For that
reason it would be much better to have a biological cure than a
cochlear implant.
- Loss of hearing comes in two phases when you age. First the number of
outer cells, which make the vibration in your ear, gets smaller. You
can still hear, but you need higher sound levels and stimulation. Next
the inner cells are affected. Those are more complicated. When you lose
those, you can't hear at all. But you can still use a cochlear implant
to stimulate the auditory nerve.
- The possible treatments for regeneration are:
1=2E Drugs, but these are very labor-intensive and use a lot of animals
2=2E Viral, introducing Atoh1 with gene therapy, but this is far away
from any clinical application at the moment
3=2E Stem cell, grafting progenitor cells with human cells to speed
things up
- Is it possible to regenerate hair cells from stem cells? There are
two populations of stem cells you can use -- embryonic and adult. The
embryonic cells grow on top of others.
- Some mouse cells were taken and transplanted to the ear in the
cochlea of a chicken embryo. From this experiment, it was learned that
it's possible to generate from embryonic stem cells a population of
progenitor cells to transplant in an embryonic cochlea.
- Now attempts are needed to try in utero stem cell therapy, injecting
stem cells. There are many roadblocks ahead and many more steps before
the science is ready for this to be done in humans.
- Drug screening for compounds that induce hearing cell regeneration in
a test tube are another approach. Researchers would like to use human
embryonic cells, but will have to adapt all they have learned from
mouse cells.
- Are there possible alternatives for embryonic stem cells? Adult stem
cells from the nervous system ("neural stem cells") didn't work well.
Others have been tried -- bone marrow, skin, etc.
- Can we find inner ear stem cells? Research found that there are stem
cells in the balance epithelia and cochlea. But the research also
discovered that there is variation in different areas. In the Organ of
Corti, cells seemed to die out fast. Vestibular system cells remained
much longer.
- The stem cells could be maintained in a lab, but it was a long and
arduous process to build, maintain and increase them. Expansion and
long-term storage isn't optional.
- Stem cells have been isolated from the ear. In the past year, they've
gone from isolating 15 cells from one to 250 cells.
- Cultures can be done of human adult hair cells so they won't have to
do human testing. This looks promising.
- Embryonic, inner ear and other stem cells all need cell delivery into
the inner ear, and safety studies must be addressed.
- Spiral ganglion cells (neurons) have an important role. If you have
these cells, you can hear with a cochlear implant. If you don't, you
cannot hear with a cochlear implant. These cells get signals from the
hair cells to the brain. In auditory neuropathy, the hair cells work
but people can't hear, and this is most likely due to the absence of
spiral ganglion cells.
- It is more complicated to replace hair cells, but replacing neurons
should be easier. Neural progenitors were grafted into a de-afferented
gerbil cochlea. This wasn't expected to work so well as it did. It's
now being studied in a
second and third batch of animals.
- Inner ear cell regeneration therapy has been and will continue to be
a long road.
- Both gene therapy and progenitor cell transplanting are in very early
experimental stages.
- Stem cell-based approaches have no alternative for human embryonic
stem cells. They are the only appropriate cell group.
- There are different flavors of hair cells. Not only are there inner
and outer ear cells, but the ear has certain frequencies.
- If gene therapy is used to regenerate cells, it would not pass to
offspring.
- Japanese researchers are testing with grafting stem cells at
different locations to see where they show up.
- Researchers have used every growth factor they could get their hands
on to try to restimulate hair cells. This is probably best. No drug has
been discovered, but a gene has.
- Dr. Heller is concerned not just about continued funding but also
about continually attracting people to the field.
Q: Drugs are being used to stimulate cell growth; have you thought
about nutrition?
A: Yes, that is done all the time. A very nutritious growing medium is
used.
Q: Where is most of the research being done?
A: About 3/4 of the inner ear regeneration is being done in the US. A
couple of groups are also working in Europe. Luckily there is a good
exchange and collaboration among researchers, not a group that is nasty
to each other.
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=A92005 by Northern Virginia Resource Center for Deaf and Hard of
Hearing Persons (NVRC), www.nvrc.org. (http://www.nvrc.org.) When
sharing this information, please ensure credit is given to NVRC
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