A team of research biologists at the Technion-Israel Institute of
Technology has succeeded for the first time in inducing human
embryonic stem cells to differentiate into the cells that make up
blood vessels, and to actually form the vessels themselves. The work
will make possible the growth of blood vessels to repair the heart
and other organs, as well as provide a way to study blood vessel
formation. Such studies could be used in developing new ways to stop
cancer, among other applications.
The team's work, led by Prof. Joseph Itskovitz-Eldor of the Faculty
of Medicine and including graduate student Sharon Gerecht-Nir is
reported in the December 15 issue of Laboratory Investigation. Prof.
Itskovitz-Eldor was among the authors of the first paper (1998)
describing embryonic stem cell technology.
Human embryonic stem cells have generated enormous excitement because
of their ability to differentiate into any of the huge variety of
cells present in the body, from nerve to muscle to liver cells.
However, it is not easy to direct the stem cells to produce a
specific cell type, which is essential if the stem cells are to be
used to repair damaged organs.
The Technion team succeeded in getting the stem cells to produce
blood vessels only by using a series of steps, each worked out with
considerable experimentation.
The first step, already developed by other researchers, was to grow
the stem cells in contact with collagen, a component of human
connective tissue. This stimulated the cells to differentiate into
mesodermic cells, one of three basic layers in the developing embryo.
Mesodermic cells give rise to blood vessel cells, nerve cells, and a
number of other types. The mesodermic cell culture consisted of a
variety of cells, each capable of differentiating into specific types
of daughter cells.
The researchers found that the cells capable of producing blood
vessels happened to be the smallest cells in the cultures. They
isolated these cells simply by filtering with a mesh fine enough to
trap the large cells, but not the smallest ones.
In a third step, these smaller cells were placed in another collagen
coated dish, where growth factors were added, which induced the
mesoderm cells to begin producing the two types of cells that go on
to build blood vessels.
"We saw that we were getting both the fragile endothelial cells that
line the blood vessels and the external vascular smooth muscle cells
that protect the vessels and control the flow of blood," explains
Prof. Itskovitz-Eldor.
In the final step, the team placed the blood vessel cells into a
"3-D" culture consisting of two kinds of gels known to promote the
growth of blood vessels. Sure enough, when the newly differentiated
cells were put into the gel, they organized themselves into small
tubes of blood vessels.
Stem-cell generated blood vessels could have some important clinical
uses. In heart bypass operations, such blood vessels could substitute
for those that now have to be transplanted from other parts of a
patient's body. In addition, experiments have shown that the cells,
injected into a mouse, spontaneously form networks of small blood
vessels, so they could improve circulation to organs that are
blood-deprived.
Researchers will also be able to study the cells to see what
chemicals can help or hinder the formation of blood vessels. In
cancer, tumors must induce cells to become blood vessels in order to
increase the tumor's own blood supply. The stem-cell-derived cultures
could show how to disrupt this process.