LENA CARLSSONīS COLUMN
Many earlier investigations of
regeneration of nerve cells (neurogenesis) are
now being questioned. This concerns among other
things reports of connections between
neurogenesis and depression, learning and stroke. (Back to Arvidīs column)
Changes
of neurogenesis are epiphenomena
There are a lot of reports
of relations between regeneration of neurons and
depressive illnesses. One hypothesis is that
stress influences the hippocampus so that
neurogenesis is reduced, which leads to
depression. The proofs are indirect. The
scientists made the observation that the volume
of the hippocampus was diminished in depression,
bipolar disorder and posttraumatic stress
disorder. These results were interpreted as being
a consequence of a reduction in neurogenesis in
the hippocampus. An increased regeneration of
nerve cells has also been reported following
antidepressives and electroconvulsive therapy in
animals.
But more and more studies of a better quality
have begun to question these relations, according
to an overview by Fritz Henn and Barbara Vollmayr
in 2004. One such study shows for instance that
no neurogenesis is required for the effect of
antidepressives. Neither was neurogenesis
increased by magnetic stimulation, which can also
counteract depression. This study utilized a
better animal model of depression than earlier
investigations. Other studies of a high quality
could not find that a reduced regeneration of
neurons led to depression or to other kinds of
altered behavior in the experimental animals.
Henn regards changes in neurogenesis as an
epiphenomenon rather than a cause of depression.
A connection between regeneration of nerve cells
and learning has also been asserted. Mice which
have been placed in an enriched environment have
been reported to change their behavior and to
have an increased neurogenesis in the
hippocampus. The mice got less anxious, adapted
faster to a new environment and learned certain
tasks in a quicker way. But if the regeneration
of neurons is blocked by irradiation, the animals
still show a changed behavior as a consequence of
the environmental enrichment, as was recently
demonstrated by Dar Meshi et al. So, according to
them, adult neurogenesis is not necessary for
learning.
Studies
using a faulty technique must be reconsidered
A special problem in many of the studies of
neurogenesis, is that a great many scientists
have used a faulty technique to detect new cells.
This concerns for instance studies of
transplantation in experimental animals and
patients with Parkinsonīs disease. In these
studies the scientists want to investigate the
fate of the transplanted cells in the brain. So
they label the cells with a substance which is a
thymidine analog and resembles thymidine, one of
the components of DNA. The thymidine analog is
also used to track newly born cells, since it is
incorporated into dividing cells where the DNA is
also replicating. Therefore the scientists have
believed that if they find a thymidine analog in
a nerve cell, this means that the nerve cell is
newly born. This is however not necessarily the
case, as it appeared.
A group lead by Catherine Verfaillie has studied
the fate of thymidine analogs in cells
transplanted in mice. The scientists found the
thymidine analog in the mouseīs own neurons. It
is well known that more than 90 percent of the
grafted cells may die after transplantation. The
thymidine analog is then released into the
environment where it may be incorporated into the
receiverīs own neurons, according to Verfaillie.
So what looks like transplanted cells are
actually the experimental animalīs own nerve
cells. As a consequence, the results of studies
of for example stem cells from bone marrow must
be reconsidered. In those studies stem cells from
bone marrow have been used in transplantations,
in order to avoid the many problems of embryonic
stem cells. The scientists have reported good
results where the stem cells evolved and
differentiated into nerve cells after the
transplantation. But since thymidine analogs were
utilized in these studies the findings must be
questioned. What looked like new nerve cells
could have been the receiverīs own neurons.
Research has also revealed that thymidine analogs
are toxic and affect the incorporating cell in
many ways. A thymidine analog may for instance
initiate a cell division, which would otherwise
not occur. The cell division is however never
completed and instead the nerve cell dies.
Thymidine analogs may also induce mutations which
change the cell surface. Among other things this
may result in a glial cell (supporting cell) of
the brain looking like a nerve cell. Thymidine
analogs may also be incorporated into dying
neurons. Hence, a cell which looks like a nerve
cell and contains a thymidine analog is not
necessarily a newly born neuron, which was
previously assumed. Therefore, many studies which
have used this technique become much more
difficult to interpret than was earlier believed.
This concerns for example Peter Erikssonīs
investigation in 1998, where he reported of
neurogenesis in the adult human brain.
No
cell division after stroke
Another example of studies which may have been
misinterpreted, because thymidine analogs were
used to label newly born neurons, concerns
stroke. In stroke, scientists have reported of an
increased neurogenesis in rats. But in a stroke
study on both adult mice and rats, Chia-Yi Kuan
and his colleagues investigated what happened to
neurons after the incorporation of the thymidine
analogs. They found that no cell division was
taking place. Certainly, the nerve cells started
to divide since the DNA synthesis began. After a
while however the neurons died without having
divided. The scientists could also demonstrate
that no thymidine analog had been incorporated in
the part of the brain where the stem cells are
situated. According to the researchers, the
stroke provokes the DNA synthesis. Juri
Katchanov, Yan Yang and many other researchers
have arrived at similar results, where brain
damages cause DNA synthesis and cell death.
Moreover, the thymidine analogs themselves seem
to be able to influence stem cells from bone
marrow, resulting in a greater number of new
nerve cells, according to Ting Yu Qu et al. The
scientists hope that this effect may be utilized
to improve the results.
It is important to know that most of the work on
"adult" neurogenesis is done in still
developing rodents which are 2-3 months old.
Rodents are not mature until at least 8 months,
which would be equivalent to "young
adults". However, the experiments relevant
to Parkinsonīs disease and Alzheimerīs disease
should be conducted in 20 month-old mice to more
closely approximate the human postmenstrual age
of 45-50 years, when these disorders usually
occur.
Human
stem cell production is a difficult task
Mostly, the debate of stem cell research in the
media is not about unsolved scientific problems
but about ethical issues concerning the use of
human embryos to create stem cell lineages. But
when it comes to making such cell lineages there
are also big difficulties which are purely
technical. It is very hard to produce human
embryonic stem cell lineages, according to a
statement in a Swedish Journal (Medicinsk
Vetenskap 4/06) by the stem cell researcher Outi
Hovatta at the Karolinska Institute. As a matter
of fact, there are no such cell lineages
containing only human material today. The
embryonic stem cells are cultivated in media
which contain animal substances. If the stem
cells shall be used in therapy in patients, the
animal material must be replaced by human
material, which is a very expensive process that
demands a great deal of work, according to
Hovatta.
January, 2007
Lena Carlsson
References
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avslöjar nya fettceller. Dagens Nyheter 15 okt
2006 (Only in Swedish)
Burns, Terry; Verfaillie, Catherine et al.
Thymidine analogs are transferred from prelabeled
donor to... Stem Cells 2006;24:1121-1127
Danielsson, Ola. Kontroversiella celler.
Medicinsk vetenskap 4/2006;26-31 (Only in
Swedish)
Eriksson PS, Gage FH et al. Neurogenesis in the
adult human hippocampus. Nat Med 1998
Nov;4(11):1207
Henn, Fritz och Vollmayr, Barbara. Neurogenesis
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Katchanov, Juri et al. Mild ischemia induces loss
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Kuan, Chia-Yi et al. Hypoxia-ischemia induces DNA
synthesis... Journal of Neuroscience
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Meshi, Dar et al. Hippocampal neurogenesis is not
required for behavioral effects of environmental
enrichment. Nature Neuroscience, published online
30 april 2006
Pearson, Helen. Stem-cell tagging shows flaws.
Nature Feb 2006;439:519
Qu, Ting Yu et al. Bromodeoxyuridine increases
multipotency... Restorative Neurology and
Neuroscience 2004;22:459-468
Rakic, Pasco. No more cortical neurons for you.
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Seress L et al. Cell formation in the human
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Yang, Yan et al. DNA replication precedes
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Đ Lena Carlsson
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