No end to endothelial cell potential

Studies examining blood vessel cells determine they could be used for regeneration and healing of organ damage

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NEW YORK—Blood vessels play a pivotal role in human biology, carrying blood, oxygen and nutrients throughout the body. Angiogenesis, the process by which new blood vessels are created, has lately become a target of interest in curtailing the spread of tumors as they seek to generate their own blood vessels to create a better environment for growth and metastasis.
But now blood vessels might also play a role in healing, as scientists at Weill Cornell Medical College have discovered that it might be possible to heal damaged or diseased organs with an injection of blood vessel cells—specifically endothelial cells, which make up the structure of blood vessels. Endothelial cells can induce regeneration in organ tissues through the release of organ-specific molecules.
This ability was discovered when the scientists decoded all the active genes in endothelial cells, highlighting hundreds that had never before been associated with them. In addition, it was also discovered that organs determine the structure and function of the blood vessels within them, as well as the repair molecules they produce.
"The work that we’ve started doing, the rationale for it was that every cell of your body is almost next to an endothelial cell, because almost every cell has to be next to a blood vessel in order to be able to receive nutrients and oxygen from it, and at the same time, have a conduit by which the end products of the metabolism [are] removed," says Dr. Sina Rabbany, adjust associate professor of genetic medicine and bioengineering in medicine at Weill Cornell Medical College. "From that perspective, it makes sense that endothelial cells, which are the building blocks of the vasculature, should be playing a much more active role, and they should not just be the ‘plumbing’ or a transportation system for delivering nutrients and removing the end products of metabolism."
“Our work suggests that that an infusion of engineered endothelial cells could engraft into injured tissue and acquire the capacity to repair the organ,” said Shahin Rafii, M.D., a professor of genetic medicine and co-director of the medical college’s Ansary Stem Cell Institute and Tri-SCI Stem Center. “These studies—along with the first molecular atlas of organ-specific blood vessel cells reported in the Developmental Cell paper—will open up a whole new chapter in translational vascular medicine and will have major therapeutic application.”
Rafii said their studies demonstrated that the endothelial cells and organs work together to repair damage. The blood vessels of a damaged organ may not be able to repair the harm themselves as they might also be damaged.
The team looked at nine different tissue types in a normal, healthy state, in addition to liver and bone marrow tissue recovering from injury. By developing technology that enabled the generation of pure populations of endothelial cells, the researchers were able to study the cells and discover that they possess tissue-specific genes that code for unique growth factors, adhesion molecules and factors that regulate metabolism.
According to Dr. Michael Ginsberg, a senior postdoctoral associate in Rafii’s laboratory during the study, blood vessels vary between organs as endothelial cells adjust to fit the various biological needs of each organ.
That variance drove the team to question how the cells can adapt to different organs, and if it might be possible to generate young endothelial cells in order to study how they are triggered to become more specialized. To investigate, the team created endothelial cells from mouse embryonic stem cells that proved to be functional, transplantable and responsive to microenvironmental signals. They can take on the characteristics of the tissue into which they’re transplanted, and when transplanted into the liver of a mouse, the generated cells matched the native cells exactly.
“These transplanted endothelial cells are being educated by the unique biophysical microenvironment organ in which they are placed. They morph into endothelial cells that belong in the organ, and that can repair it,” said Rabbany. “If you have a heart injury and you need to reform some of your cardiomyocytes, the endothelial cells that are around the heart secrete factors that are specific for helping a heart repair itself.”
More work is necessary before this approach can be moved to the clinic, however. The team is working to produce endothelial cells that are immunologically compatible with the patient that would receive them. Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, as well as a co-author on the studies, noted that such cells “could be derived from human embryonic pluripotent stem cells as well as by somatic cell nuclear transfer.”
In translating this approach into the clinic and humans, Rafii notes that the biggest issue for them to solve is “the problem of immunogenicity.”
“Endothelial transplantation for organ regeneration requires that endothelial cells genetically match the patient who is being transplanted for organ regeneration,” Rafii explains, adding that they don’t know yet how much of a match is required to prevent rejection. Along those lines, they need to either develop technology to enable the generation and harvesting of autologous endothelial cells from patients, establish a biobank in which endothelial cells of multiple types can be stored or harvest fibroblasts from patients that can them be reprogrammed into endothelial cells.
Endothelial cells hold potential beyond healing organ damage as well, as Rafii called their potential endless, noting they can also be used “as Trojan horses to block tumor growth, they could be altered to carry toxic chemicals. They could become biological cruise missiles, directed to do many things inside diseased organs.”
Rabbany adds that this discovery and the use of endothelial cells in regeneration represent "a paradigm shift," moving away from the traditional approach of transplanting entire organs--a practice that constantly faces the issue of a lack of available organs--and toward an approach that seeks to repair damage instead.
“Our work has just begun,” said Rafii.

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