Long-Lasting Blood Vessels Regenerated from Reprogrammed Human Cells

Researchers from Massachusetts General Hospital (MGH) in Boston, MA have used human induced pluripotent stem cells to make vascular precursor cells to produce functional blood vessels that lasted as long as nine months.

Rakesh Jain, director of the Steele Laboratory for Tumor Biology at MGH and his team derived human induced pluripotent stem cells (iPSCs) from adult cells of two different groups of patients. One group of individuals were healthy and the second group had type 1 diabetes. Remember that iPSCs are derived from adult cells through the process of genetic engineering. By introducing specific genes into these adult cells, the adult cells are de-differentiated into an embryonic-like state. The embryonic-like cells can be cultured and grown into a cell line that can be differentiated into various cell types in the laboratory. These differentiated cells types can then be transplanted into laboratory animals for regenerative purposes.

“The discovery of ways to bring mature cells back to a ‘stem-like’ state that ca differentiate into many different types of tissue has brought enormous potential to the field of cell-based regenerative medicine, but the challenge of deriving functional cells from these iPSCs still remains,” said Rakesh. “our team has developed an efficient method to generate vascular precursor cells from human iPSCs and used them to create networks of engineered blood vessels in living mice.”

The ability to regenerate or repair blood vessels could be a coup for regenerative medicine. Cardiovascular disease, for example, continues to be the number one cause of death in the United States and other conditions caused by blood vessel damage (e.g., the vascular complications of diabetes) continue to cause a great deal of morbidity and mortality each year. Also, providing a blood supply to newly generated tissue remains one of the greatest barriers to building solid organs through tissue engineering.

Some studies have used iPSCs to build endothelial cells (the cells that line blood vessels), and connective tissue cells that provide structural support. These cells, unfortunately, tend to not produce long-lasting vessels once they are introduced into laboratory animals. A collaborator with Jain, Dai Fukumura, stated, “The biggest challenge we faced during the early phase of this project was establishing a reliable protocol to generate endothelial cell lines that produced great quantities or precursor cells that could generate durable blood vessels.”

Jain’s group adapted a protocol that was originally designed to derived endothelial cells from human embryonic stem cells. They isolated cells based on the presence of more than one cell surface protein that marked out vascular potential. Then they expanded this population of cells using a culture system developed with embryonic stem cells that had been differentiated into endothelial cells. Further experiments confirmed that only those iPSCs that expressed all three cell surface proteins on their surfaces had the potential to form blood vessels.

To test the capacity of those cells to generate blood vessels, they implanted them onto the surface of the brain of mice in combination with mesenchymal precursors that generate smooth muscles that surround blood vessels.

Within two weeks after transplantation, the implanted cells had formed entire networks of blood vessels with blood flowing through them that has also fused with the already existing blood vessels. These engineered blood vessels continued to function for as long as 280 days in the living animal. Implantation under the skin, however, was a different story. It took 5 times the number of cells to get them to form blood vessels and they were short-lived. This is similar to the results observed in other studies.

Because type 1 diabetes can ravage blood vessels, Jain’s team made iPSCs from patients with type 1 diabetes to determine if iPSCs from such patients would generate functional blood vessels. Similarly to the cells generated from healthy individuals, vascular precursors generated from type 1 diabetics were able to form long-lasting blood vessels. However, these same cell lines showed variability in their ability to form vascular precursors. The reason for this is uncertain.

Rekha Samuel, one of the lead authors of this paper, said “The potential applications of iPSC-generated blood vessels are broad – from repairing damaged vessels supplying the heart or brain to preventing the need to amputate limbs because of the vascular complications of diabetes. But first we need to deal with such challenges as the variability of iPSC lines and the long-term safety issues involved in the use of these cells, which are being addressed by researchers around the world. We need better ways of engineering the specific type of endothelial cell needed for specific organs and functions.”

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).