Not All Embryonic Stem Cell Lines Are Created Equal
Science Daily — When it comes to generating neurons, researchers have
found that not all embryonic stem (ES) cell lines are equal. In
comparing neurons generated from two NIH-approved embryonic stem cell
lines, scientists have uncovered significant differences in the
mature, functioning neurons generated from each line.
The discovery implies that culture conditions during ES cell
generation -- which have yet to be identified -- can influence the
developmental properties of human ES cells.
The report, which was published August 6, 2007, in the early online
edition of the Proceedings of the National Academy of Sciences, also
describes a new technique for producing functioning neurons from stem
cells that will be important for creating models of human
neurodegenerative diseases.
The research team was led by UCLA stem cell biologist Yi Sun and
Howard Hughes Medical Institute investigator Thomas Südhof at the
University of Texas Southwestern Medical Center at Dallas.
Embryonic stem cells are developmentally immature cells that are
capable of self-renewal and of differentiating into any type of
tissue in the body. Researchers believe they hold the potential for
generating neural, cardiac and other cells that can be implanted to
restored damaged tissue.
"To the best of my knowledge, until now there have been few
functional studies of the neurons derived from embryonic stem cells,"
said Südhof. "People in the field have traditionally been interested
in whether they can make neurons and what molecular markers
characterize those neurons. However, because different embryonic stem
cell lines were derived under diverse conditions, the possibility
existed that cell lines would produce neurons with distinct
properties."
The researchers compared mature neurons grown from two embryonic stem
cell lines approved for research by the National Institute of Health.
Sun and her colleagues developed procedures to differentiate the two
stem cell lines first into neural progenitor cells, and then into
mature neurons. They were also able to purify those neurons for
study.
To probe how the neurons functioned, the researchers developed a
culture technique that induced the newly produced neurons to
establish synapses with one another. Synapses are the critical
junctions between neurons where much of the signaling and
communication between neural cells occurs.
Through functional analyses of these neurons, Sun, Südhof and their
colleagues found that the two ES cell lines differentiated into two
distinct types of neurons that are actually found in different parts
of the brain.
The researchers next performed electrophysiologica
synaptic connections between the neurons. "We found that the neurons
derived from the two cell lines have completely different properties
in terms of what type of synapses they develop and at what time
course this happens during culture," said Südhof. Furthermore, the
studies showed that the neurons derived from the two cell lines used
different chemicals called neurotransmitters to communicate with one
another, he said.
Sun and her colleagues compared the microRNAs produced by the two
types of neurons. MicroRNAs are small snippets of genetic material
that are believed to be significant regulators of stem cell
differentiation.
"It's been proposed that microRNAs might be part of the defining
signatures for human ES cells, and many are expressed in the brain,"
said Sun. "It was comforting that our analysis showed that as the ES
cells matured into neural progenitors and neurons, the expression of
the microRNAs genes specific to ES cells dropped thousands of times,
and those specific to brain cells increased thousands of times. But
on the other hand, when we compared the two lines, we found
differences in microRNA gene expression that might contribute to this
neuronal bias in the lines," she said. Südhof said that the
differences among ES cell lines could have implications for potential
treatments using the cells.
"It's clear that if you're going to treat a motor neuron disease, you
need those types of neurons; whereas if you want to treat a forebrain
disease like Huntington's, you need ES cells that differentiate into
that type of neuron," he said.
The differences in neurons produced by cell lines may offer both
advantages and disadvantages for treatment, he said. "On the one
hand, it may actually be good to have ES cells with a particular
propensity for differentiation, because it may make it easier to get
certain types of tissue. On the other hand, it may also limit the
ability of these ES cells to fully replicate those types of tissues."
Sun said that her technique for differentiating ES cells into mature
neurons is likely to have important future research
applications. "This technique enables us to produce pure cultures of
functioning human neurons that we can genetically manipulate to mimic
human disorders," she said. "Before, it was only possible to use
mouse or other animal cells to model neurodegenerative diseases, but
the genetic background is so different from that of humans that key
aspects of diseases such as Alzheimer's could not be reproduced."
Both Sun and Südhof said that their findings have implications for
the production of ES cell lines. "There is absolutely no question
that these findings mean that there need to be more embryonic stem
cell lines for research purposes and for use in potential
treatments," said Südhof.
Sun said that developing more ES cell lines is important "because
right now we still don't know the causes for the functional
differences we found. Understanding the causes will require more cell
lines for study. And once we understand the causes, we can take them
into account in generating new cell lines that will be better defined
and enable more reproducible applications.
Note: This story has been adapted from a news release issued by
Howard Hughes Medical Institute.
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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