May 02, 2002
Astrocytes Trigger Maturation of Neural Stem Cells
Researchers have discovered that astrocytes — brain cells once
thought to be little more than a component of the supportive scaffold
for neurons — may actually play a starring role in triggering the
maturation and proliferation of adult neural stem cells. The studies
also suggest that growth factors produced by astrocytes may be critical
in regenerating brain or spinal tissue that has been damaged by trauma
or disease.
The discovery that astrocytes are important for neuronal maturation,
or neurogenesis, was reported in the May 2, 2002, issue of the journal
Nature by Howard Hughes Medical Institute investigator Charles
F. Stevens and colleagues Fred H. Gage and HHMI research associate
Hong-jun Song at The Salk Institute.
“While it is only speculation at this point, it may be that spinal cords fail to regenerate not because the stem cells aren't there, but because there is something missing in their glial cells.”
Charles F. Stevens
Neurons are the key information-carrying cells in the central
nervous system. All neurons, as well as other types of brain cells,
arise from immature neural stem cells, which have the potential to
develop into any kind of cell in the central nervous system.
According to Stevens, astrocytes have not traditionally been thought
to be involved in neurogenesis. "Astrocytes, so-named because of their
starlike shape, are glial cells, a term which is derived from the Latin
word for 'glue,'" explained Stevens. "They fill in the space between
neurons, and they have long been known to have a supportive role, which
includes taking up neurotransmitters released by neurons. They also
maintain the extracellular environment with the right concentrations of
chemicals to support neurons."
Recently, however, evidence emerged that astrocytes might actually
be "instructing" stem cells about which developmental pathway to
select, said Stevens. For example, Stevens and his colleagues reported
in a previous research article that adult neuronal stem cells
proliferated more readily when they were cultured with astrocytes
rather than on a layer of fibroblast cells.
Stevens said that at first it seemed likely that the astrocytes
might be keeping the stem cells alive longer or encouraging
proliferation. In other words, they might be merely supporting the
cells in becoming functional neurons, Stevens said.
"Another possibility was that the astrocytes were somehow actually
instructing the stem cells to divide and adopt a neuronal fate," he
said. "This seemed least likely because when the embryonic brain is
growing, most of the neurons are born before the glia, so one wouldn't
have thought glia were instructing stem cells."
To define the astrocytes’ contribution to neuronal
development, Song, Stevens and Gage tagged adult neural stem cells with
a green fluorescent marker so they could follow the development of
those cells. When they grew the tagged stem cells in cell culture with
both astrocytes and other neurons, the stem cells readily developed
into mature neurons. However, when the scientists grew the tagged stem
cells in cultures enriched with astrocytes, they found that the
astrocytes supported the growth of many more neurons from the stem
cells.
A big question, said Stevens, was whether the astrocytes influenced
neuronal growth by releasing chemicals or by direct contact with the
stem cells. So, the scientists cultured neural stem cells so that they
could not touch the astrocytes, or so that the astrocytes were gently
killed and could not release regulatory chemicals. The experiments
showed that in both cases, the astrocytes triggered stem cell
development. This suggests that astrocytes trigger neuronal growth both
by releasing chemicals and through a contact-related signal, Stevens
said.
Mathematical analysis of the cells in culture revealed that
astrocytes encouraged both stem cell proliferation and their maturation
into neurons. "We found that stem cells grown on glia divided about
twice as fast as they did when grown on fibroblasts," said Stevens.
"Glia make a good environment to instruct them to divide.
"But the big surprise was that the stem cells were adopting a
neuronal fate at about six times the rate they were on fibroblasts,"
said Stevens. "The astrocytes either instruct the progenitors to adopt
a neuronal fate or form an environment that induces or permits that
fate. We're not exactly sure what word to use, because we don't know
what the mechanism is," he said.
In additional experiments, the researchers found that adult
astrocytes were about half as effective as embryonic astrocytes in
promoting neurogenesis in adult neural stem cells.
One intriguing implication of the experiments, said Stevens, is that
astrocytes’ involvement in neuronal growth regulation might
explain why neural stem cells can regenerate neurons in areas of the
brain such as the hippocampus, but not in the spinal cord, where they
mature into glial cells.
"It was surprising to us that the stained stem cells from the
hippocampus would only produce neurons when grown on glia from the
hippocampus, but they hardly made any neurons at all when we grew them
on glia from the spinal cord," said Stevens.
"While it is only speculation at this point, it may be that spinal
cords fail to regenerate not because the stem cells aren't there, but
because there is something missing in their glial cells. Thus,
developing spinal cord regeneration therapies might mean supplying some
factor produced by glial cells," said Stevens.
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