Researchers have developed a new technique -- and described a novel mechanism -- for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. Endothelial cells form the interior "lining" of all blood vessels and are the main component of capillaries, the smallest and most abundant vessels.
The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells -- more than 40-fold the quantity possible with previous approaches.
"This technique is the first of its kind with serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes," said Dr. Shahin Rafii, the study's senior author and Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College. Dr. Rafii is also an investigator of the Howard Hughes Medical Institute.
Researchers first screened for molecular factors that come into play when stem cells turn into endothelial cells. Their findings led them to a strategy that significantly boosts the efficiency of producing these cells.
They then tracked the differentiation process in real-time using a green fluorescent protein marker developed by Dr. Daylon James, the study's first author and assistant research professor in the Department of Reproductive of Medicine at Weill Cornell Medical College. They found that when they exposed stem cells to a compound that blocks TGF-beta (a growth factor involved in cell specialization) at just the right time during cell culturing, the propagation of endothelial cells dramatically increased.
Even more striking, they found that the cells worked properly when injected into mice. The cells were quickly assimilated into the animals' circulatory systems, and functioned alongside normal vasculature.
The use of vascular cells in regenerative medicine has had to overcome the necessity of proper in vivo assembly of new blood vessels from stem-cell-derived cells, according to Dr. Sina Rabbany, adjunct professor at Weill Cornell Medical College and professor of bioengineering at Hofstra University. In addition to manipulating biological factors implicated in endothelial cell differentiation, the impact of blood flow on endothelial cells is critical to engineering durable, vascularized organs.
Another obstacle to the clinical use of cultured endothelial cells is the potential of immune rejection when the cells are injected into a patient. To address this risk, one approach would be to create a large, genetically diverse bank of human embryonic stem cells that, on demand, could be converted into endothelial cells that are compatible with specific patients.
With the plentiful supply of endothelial cells that the new methods provide, Dr. Rabbany's team is working to build biological scaffolds that model the microenvironment of the vasculature, so that the vessels they generate will be functional and long-lasting in patients.
The current study sheds light on the generation of human embryonic vasculature in ways that have not previously been feasible due to obstacles associated with the use of human embryonic tissue. Said Dr. James, "The unbiased screening technique we used is a major technological advance that opens up possibilities for discovery of how human embryonic stem cells morph into the specific mature cells that compose the brain, liver, pancreas, and so on. Our general approach can be applied to additional human tissues and help other stem cell research groups develop and maintain specialized cell types in the larger effort to understand human development -- and to heal many different kinds of human diseases and injuries."
Adapted from the Weill Cornell medical center announcement.
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