Stem Cell Research Shows Early Steps in Human Development
By Audrey Huang
Johns Hopkins Medicine
Researchers at Johns Hopkins, using human embryonic stem cells, have
uncovered the molecular underpinnings of one of the earliest steps in
human development. Their identification of a critical signal mediated
by the protein BMP-4 that drives the differentiation of stem cells
into what will become the placenta is published in the April issue of
Cell Stem Cell.
The finding, they say, also highlights one aspect of human cell
biology that has not been replicated in other animal model systems.
And it is virtually impossible to use anything other than human
embryonic stem cells to gather information of this kind.
One reason for the excitement, the investigators say, is that the
system can provide a research model to study very early human
development, including the formation of the placenta, which develops
from the same early embryo.
"The finding was serendipitous and at the same time a very important
addition to our understanding of early human development,
Linzhao Cheng, an associate professor of gynecology and obstetrics
and co-director of the stem cell program of the Johns Hopkins
Institute for Cell Engineering. "This is one area of stem cell
biology where human and mouse differ significantly, and we never
would have discovered this if we had limited our studies to using
only mouse embryonic stem cells. Adult human stem cells just didn't
work for this."
The research team uncovered their find during efforts to study a rare
human blood disorder caused by mutations in a gene called PIG-A.
According to Cheng, a good model to study the disease does not exist
as engineered mice without the gene either die before birth, or do
not reproduce symptoms found in patients. So, using a conventional
genetic engineering tool, the researchers tried for years —
literally — to knock out PIG-A in adult stem cells, without success.
They then turned to knocking out PIG-A in human embryonic stem cells.
"Only with the human embryonic stem cells could we grow out the rare
cells engineered to lack PIG-A," Cheng said. The result was the
growth of two human embryonic stem cell lines that lack PIG-A and
therefore do not contain any proteins known as
glycosylphosphatidy
GPI anchor proteins attach many different types of proteins involved
in cell communication to a cell's outside surface. Without certain
GPI proteins, cells may not function properly.
Then the researchers took one more step to verify that their
engineered embryonic stem cells behaved like normal stem cells. "We
just wanted to make sure that our knockout cells could still
differentiate and specialize," Cheng said.
One of the earliest steps of embryonic stem cell differentiation in
normal embryonic development is the development of the trophoblast, a
layer of seed cells that later develops into the placenta.
Trophoblast differentiation, according to Cheng, occurs when
embryonic stem cells are exposed to BMP-4 protein, either naturally
or in the lab.
To their surprise, however, when they treated their knockout cells
with BMP-4, the cells did not become trophoblasts.
Only when they added the PIG-A gene back into their cells did BMP-4
do its work and cause the cells to become trophoblasts, allowing the
researchers to conclude that trophoblast differentiation depends on
certain cell surface proteins to receive the BMP-4 signal.
The research was funded by the National Institutes of Health and
Johns Hopkins Institute for Cell Engineering.
Authors on the paper are Guibin Chen, Zhaohui Ye, Xiaobing Yu,
Jizhong Zou, Prashant Mali, Robert Brodsky and Cheng, all of Johns
Hopkins
http://www.jhu.
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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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