Main Category: Stem Cell Research
Also Included In: Blood / Hematology
Article Date: 11 Oct 2013 – 0:00 PDT

These findings raise the question as to how endothelial cells have the capacity to adapt to the biological demands of each organ. Is it possible to design “immature” endothelial cells that could allow scientists to identify the means by which the microenvironmental cues educate them to become more specialized endothelial cells?

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In fact, in the Developmental Cell study, the researchers transplanted these generic endothelial cells generated by Dr. Rabbany’s team into the liver of a mouse and found that it became indistinguishable from native endothelial cells. This also occurred when cells were grafted into kidneys. “These naive endothelial cells acquire the phenotype — the molecular profile and signature — of the native pre-existing endothelial cells due to the unique microenvironment in the organ,” Dr. Ginsberg says.

Together, the studies show that endothelial cells and the organs they are transplanted into work together to repair damage and restore function, says the study’s lead investigator, 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. When an organ is injured, its blood vessels may not be able to repair the damage on their own because they may themselves be harmed or inflamed, says Dr. Rafii, who is also an investigator at the Howard Hughes Medical Institute.

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To address this issue, the scientists postulated that endothelial cells derived from embryonic stem cells could behave as resilient endothelial cells, being able to be taught how to act like an organ-specific blood vessel. Indeed, in the Stem Cell Journal study, the team generated endothelial cells from mouse embryonic stem cells that were functional, transplantable and responsive to microenvironmental signals.

“Scientists had thought blood vessels in each organ are the same, that they exist to deliver oxygen and nutrients. But they are very different,” and each organ is endowed with blood vessels with unique shape and function and delegated with the difficult task of complying with the metabolic demands of that organ, Dr. Rafii adds.

They found that endothelial cells possess tissue-specific genes that code for unique growth factors, adhesion molecules, and factors regulating metabolism. “We knew that these gene products were critical to the health of a particular tissue, but before our study it was not appreciated that these factors originate in the endothelial cells,” Dr. Nolan says.

Creating an endothelial cell genetic ‘atlas’

In the Developmental Cell study, the research team examined nine different tissues at homeostasis — a steady, healthy state — as well as liver and bone marrow recovering from a traumatic injury.

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Studies suggest infusion of blood vessel cells may contribute to organ regeneration in the future

Additionally, Brisa Palikuqi, Michael G. Poulos, William Schachterle,Ying Liu, Zev Rosenwaks, Jason M. Butler, Jenny Xiang, Arash Rafii and Koji Shido, all from Weill Cornell Medical College, participated in the Developmental Cell study.

Dr. Rabbany says researchers can propagate these cells in large numbers in the laboratory. “We now know what it takes to keep these cells healthy, stable and viable for transplantation,” he says.

“We also found that the healing, or regeneration of tissue, in the liver and in the bone marrow were unexpectedly different — including the repair molecules, known as angiocrine growth factors, that were expressed by the endothelial cells,” says Dr. Olivier Elemento, who performed the complex computational calculations for the studies.

However, to translate these studies to the clinical setting the scientists have to generate endothelial cells that have similar immune constitution – “immunocompatible” with the recipient patient. “Endothelial cells could be derived from human embryonic pluripotent stem cells as well as by somatic cell nuclear transfer (SCNT),” says 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 and a co-author on the studies. “In the SCNT approach, the nucleus of a somatic cell is introduced into the human egg resulting in the generation of embryonic stem cells that would generate endothelial cells that are a genetic match of the patient,” says Dr. Daylon James, assistant professor of reproductive biology at Weill Cornell, who was instrumental in designing protocols to generate endothelial cells from human embryonic stem cells.

Ginsberg and Nolan received salary support from Angiocrine Biosciences after becoming employees. The Weill Cornell Center for Technology Enterprise and Commercialization has filed a patent application on inventions emanating from the material covered in the Developmental Cell paper and that Ginsberg and Nolan are inventors on.

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Blood vessels differ among various organs because the endothelial cells have to constantly adapt to the metabolic, biomechanical, inflammatory and immunological needs of that particular organ, says Dr. Michael Ginsberg, a senior postdoctoral associate in Dr. Rafii’s laboratory during this study. Ginsberg also became an employee of Angiocrine Bioscience after the study ended. “And we have now found how endothelial cells have learned to behave differently in each organ and adjust to the needs of those organs,” he says.

In studies appearing in recent issues of Stem Cell Journal and Developmental Cell, the researchers show that endothelial cells — the cells that make up the structure of blood vessels — are powerful biological machines that drive regeneration in organ tissues by releasing beneficial, organ-specific molecules.

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Weill Cornell Medical College. “Studies suggest infusion of blood vessel cells may contribute to organ regeneration in the future.” Medical News Today. MediLexicon, Intl., 11 Oct. 2013. Web.
13 Oct. 2013. <http://www.medicalnewstoday.com/releases/267227.php>

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From these cells, they were able to take a snapshot of all the genes that are being expressed in the various populations of endothelial cells known as vascular beds.

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