The Origins of Regenerated Hair Cells
by Cheryl Heppner
Dr. Matthew W. Kelley
National Institute on Deafness and Other Communication Disorders,
National Institutes of Health
- There are many cause of hearing loss, but in most cases it's due to
the loss of specialized hair cells. Supporting cells are also important
in hearing for "potassium recycling."
- People who have mutations in genes that are only turned on in hair
cells are hard of hearing or deaf. People with mutations in genes that
are only turned on in support cells are also hard of hearing or deaf.
- To restore hearing requires the replacement of both hair cells and
support cells. We must discover the instructions required to make the
hair cells and support cells, which exist in the form of genes located
in every cell.
- Every cell has a nucleus. Inside the nucleus are chromosomes made
up of DNA strands. Parts of these strands make up genes.
- Genes that make hair cells have criteria, such as turning on other
genes or turning on very early in the form of hair cells.
- Atoh1 is the gene that meets all the criteria. Studies in animals
have shown that without Atoh1, animals can't make hair cells.
- In the lab, scientists have used gene transfer to put Atoh1 closer
to the cochlea. The cells seem to be hair cells.
- Atoh1 seems to be a very important gene. Earlier this year in a
University of Michigan study by Dr. Yeohash Raphael, gene therapy was
used to introduce Atoh1 in guinea pigs deafened by chemicals. This has
given promising results so far, as some animals had improved hearing.
- So what about the supporting cells? Every hair cell is supported by
a surrounding circle of supporting cells. It looks like the hair cells
will go ahead and make the supporting cells, so we may not need to find
a gene for supporting cells.
- It may be possible to use this approach to restore hearing, using
gene transfer of Atoh1 to trick or coerce the development of missing
cells.
Q: How can I be a human guinea pig for this experiment?
A: Dr. Raphael will be the one to move forward with that.
Q: Would a potassium deficiency be responsible for the loss of hair
cells?
A: Probably not, because a potassium deficiency would cause the loss of
many other functions before affecting hearing.
Q: How do you do the gene transfer?
A: An electric charge is applied and little copies of Atoh1 are made.
The electrical shock seems to stimulate them. Dr. Raphael uses a
modified form of a virus.
Q: Will people who have a cochlear implant be candidates for this?
A: This is best answered by a surgeon, but being less of a candidate
might be a concern for those considering bilateral implants.
Dr. Neil Segil
House Ear Institute and Keck School of Medicine, University of Southern
California
- Losing hair cells can happen through a lot of circumstances such as
loud music, chemicals, antibiotics, and chemotherapy.
- When hair cells are lost, supporting cells will come up and
surround them.
- The problem with regeneration is that it doesn't happen in humans
and warm-blooded animals in general.
- Options for regeneration are:
1. To stimulate existing stem cells with progenitors (healing from
within)
2. To transplant using stem cells or progenitors -- if we could figure
out what the cells and progenitors look like.
- In birds and lizards, when the hair cells die, remaining hair cells
grow new ones. Why can't mammals regenerate? The hair cells in our ears
don't divide. Scientists are trying to learn why -- do they lack the
capacity, are they missing a signal, or are they not there?
- They decided to go back to the embryo stage to see if there are
clues that would answer these questions. They looked at how cells know
when to stop dividing in an embryo. Every cell, in dividing, has to go
through a complicated process where a lot can go wrong. Studies were
done with two groups of cells that inhibit or stop cells from dividing.
- They looked at mouse embryos as an ear was forming and found that
cells stopped dividing at a very specific time. They now think that a
protein called p27(Kip1) controls that and tells them when to stop.
- If you take p27(Kip1) from a mouse, you get an abnormal inner ear
with overproduction of hair and support cells. They still stop dividing
after one or two more divisions but the effect is still that it's
disorganized.
- This seems to indicate that there is a mechanical function involved
in deafness. This is a caution for us in hair cell regeneration; it may
not be enough in trying to restore hearing if we just get them to come
back.
- Prior to these studies, we didn't know if the supporting cells
retained the ability to divide, differentiate, etc. Using fluorescent
light to isolate it, p27(Kip1) was collected. The cells were from a
mouse that had just been born, and these cells were still developing.
This procedure showed that the cells were in fact turning into hair
cells. Now studies need to be done to see if the same result can be
obtained in older animals.
Q: Is any research being done on human fetuses or embryos?
A: This research is still in an early stage. At some point this will be
needed, if results continue to be promising.
Q: Is there any sign of differences in non-mammalian hair cell
structure?
A: There are many significant ones. Mammal cells are much more derived
and have more differentiation and structure.
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(c)2005 by Northern Virginia Resource Center for Deaf and Hard of
Hearing Persons (NVRC), www.nvrc.org. When sharing this information,
please ensure credit is given to NVRC.
