In a significant step toward restoring healthy blood circulation to treat a variety of diseases, a team of scientists at Weill Cornell Medical College (WCMC) has developed a new technique for turning human embryonic stem cells into plentiful, functional endothelial cells. Such cells form the interior "lining" of all blood vessels and are the main component of capillaries. In the near future, the researchers believe, it will be possible to inject these cells into humans to heal damaged organs and tissues.
The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells -- over 40 times more than previous approaches can develop. The approach may also yield new ways to study genetically inherited vascular diseases.
The study appears in the advance online issue of Nature Biotechnology.
"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," says Dr. Shahin Rafii, the study's senior author and the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at WCMC.
In recent years, enormous hopes have been pinned on stem cells as the source of future cures and treatments. Indeed, human embryonic stem cells have the potential to become any one of the more than 200 types of adult cells. However, the factors and pathways that govern their differentiation to abundant derivatives that could be used to repair organs have remained poorly understood.
A major challenge for Rafii's lab has been to improve their understanding, and hence control, of how stem cells convert to various cell types (the differentiation process), and then to generate enough vascular endothelial cells -- many millions -- so they can be used therapeutically.
To meet this challenge, the scientists 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.
Then, the researchers tracked the differentiation process in real-time using a green fluorescent protein marker developed by Daylon James, the study's first author and assistant research professor in reproductive of medicine at WCMC. They found that when they exposed stem cells to a compound that blocks 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.
With the plentiful supply of endothelial cells that the new methods provide, Sina Rabbany, an adjunct professor at WCMC, 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.
Another major obstacle to 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.
The new endothelial cell culture is currently being validated in ongoing research at WCMC using a number of stem cell "lines." Using the new differentiation methods, several of these new embryonic stem cell lines have been turned into vascular cells.
Testing in humans to restore blood supply to injured organs is the next major step.
Contact: Andrew Klein
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