October 10, 2000
Study Reveals How Growth Factors Affect Human Stem Cells
Researchers have begun to probe the effects that growth factors have
on the differentiation of human embryonic stem cells. According to the
researchers, their efforts represent a step toward understanding how to
direct human embryonic stem cells to become the more specialized cells
that make up specific tissues such as brain and muscle.
In a research article published in the October 10, 2000, issue of
Proceedings of the National Academy of Sciences, research teams
led by Howard Hughes Medical Institute investigator Douglas A. Melton and
Hebrew University geneticist Nissim Benvenisty report that they applied
eight growth factors to cultured human embryonic stem cells to observe
their effects on cell differentiation.
“While we have demonstrated the potential for directing the differentiation of these cells for use in cell replacement therapy, even in the best case, this represents only an initial step forward.”
Douglas A. Melton
Human embryonic stem cells are undifferentiated cells that can
develop into any of the specialized cell types found in the human body.
Their developmental fate is influenced by the activity of a number of
cellular signals, including growth factors. "Until now, no one had
reported extensive and systematic studies on human embryonic stem
cells," said Melton, who is at Harvard University. Other research teams
had performed similar studies on mouse embryonic stem cells, but
Melton, Benvenisty and their colleagues saw the need to do a more
comprehensive, systematic analysis of the effects of growth factors on
the differentiation of human embryonic stem cells.
By applying each of the eight growth factors to the cultured stem
cells, the researchers were able to follow the developmental path that
the cells chose while under the influence of a specific growth factor.
The studies showed that each of the growth factors elicited subtle
differences in effect. While none of the growth factors unequivocally
directed development of differentiation toward a specific cell lineage,
the studies hint that a combination and timing of growth factors might
achieve such an end.
Melton emphasized that the choice of growth factors was a practical
one and by no means represents the broad spectrum of growth factors
that might govern stem cell differentiation. "While we have
demonstrated the potential for directing the differentiation of these
cells for use in cell replacement therapy, even in the best case, this
represents only an initial step forward," he said. "Besides choosing
those growth factors that were available, we chose those for which we
could detect receptors on the surface of the cells. There was no sense
in adding a growth factor if the cells didn't express a receptor for
that growth factor."
The growth factors directed the stem cells to differentiate into
three different categories—endodermal, ectodermal and mesodermal.
Endodermal cells give rise to the liver and pancreas; ectodermal cells
become brain, skin and adrenal tissues; and mesodermal cells become
muscle. Furthermore, the researchers found that they could categorize
the growth factors based on their effects on differentiation. One group
of growth factors appeared to inhibit endodermal and ectodermal cells,
but allowed differentiation into mesodermal cells. A second group
induced differentiation into ectodermal and mesodermal cells, and a
third group allowed differentiation into all three embryonic
lineages.
"When an egg cell divides, it doesn't immediately tell its daughter
cells to become nerve, brain or pancreatic cells," said Melton.
"Rather, it first parses cells into the three general territories (germ
layers)—ectoderm, mesoderm and endoderm. And, our studies showed
that the growth factors encourage cells to develop into more of one
germ layer and less of the other two.
"In the best of all possible worlds, one would like to find growth
factors could be added to a human embryonic stem cell to make it become
a cardiomyocyte to replace defective heart muscle or a pancreatic beta
cell for transplantation into diabetics," said Melton. "But these
studies strongly suggest that finding such a factor will be exceedingly
unlikely."
Also, said Melton, the finding that most of the growth factors
inhibit differentiation of specific cell types suggests that use of
growth factor inhibitors might prove as important as inducers in
directing stem cell differentiation. Ultimately, he said, controlling
stem cell differentiation will likely involve a strategy that employs
multiple growth factors in a certain order and at certain times.
"It may be a bit like educating a child, in which you don't
designate children in kindergarten as doctors, lawyers or surgeons, but
you give them some kind of general education. And, as they progress and
show an interest in a specific field, you give them a more specialized
education."
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