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News — 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.

NIH SupportThe Technion team has become one of the world's leading groups for stem cell research and has received considerable support from the U.S. NationalInstitutes of Health (NIH).

Of three grants totaling $2.5 million for 3 years, one is for expanding research into growing blood vessel cells, which have already been successfully grown at the Technion. Another grant is for developing joint education programs in stem cell technology with NIH scientists. The courses will be taught at the NIH and at the Technion. The third grant is for infrastructure to house stem cell research.

The Technion-Israel Institute of Technology is Israel's leading science and technology university. It commands a worldwide reputation for its pioneering work in computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel's high-tech companies are alumni. Based in New York City, the American Technion Society is the leading American organization supporting higher education in Israel, with more than 20,000 supporters and 17 offices around the country.