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Cornell researchers reprogram amniotic fluid cells to treat vascular diseases
NEW YORK—In a study that could be a game-changer in the field of stem cell research, a team from Weill Cornell Medical College has discovered a way to successfully reprogram diagnostic prenatal amniocentesis cells into abundant, stable endothelial cells that can regenerate and repair damaged blood vessels and heart tissue.
The study, published Oct. 18 in the journal Cell, presents an exciting new alternative to the controversial use of human embryonic stem cells (hESCs) and some of the proliferation or safety issues encountered when using them or other types of cells.
"Some of the controversy and problems we have with stem cell research can be overcome by looking at different cell resources," says Dr. Michael Ginsburg, a senior postdoctoral associate in the laboratory of Dr. Shahin Rafii at Cornell. "We are really excited about finding a novel way of possibly improving the techniques used in the endeavor of regenerative medicine."
Previous attempts to clinically produce endothelial cells that can be used to treat patients have failed because isolation of these cells from adult organs is inefficient. Scientists have fared no better by attempting to produce cells from the body's master pluripotent stem cells. Experiments using these cells, which can become any cell in the body, did in fact produce endothelial cells—but they often grew poorly, could not be fully differentiated or even caused tumor growth.
That isn't the case with the cells used in the Cornell study, Ginsburg quickly notes. The cells were collected during routine mid-pregnancy amniocentesis procedures with the permission of the expectant mother. Ginsburg stresses that these cells are not embryonic.
"These are mostly cells sloughed off the fetus. They are floating around, and not capable of being turned into a new fetus or anything," he says. "There is no harm to the baby or to the mother. It turns out, we can take these cells out and grow them in culture like any other cell type."
And that is precisely what the research team did, turning to human amniotic fluid-derived cells, which some studies had suggested have the potential to become differentiated cell types—if stimulated in the right way.
"We showed that we can start with 100,000 amniotic cells and within four to five weeks, produce 6.5 billion cells," says Ginsburg.
The researchers looked for the genes that hESCs use to differentiate into endothelial cells, identifying three genes that are expressed during vascular development: members of the "E-Twenty-Six" (ETS) family of transcription factors known to regulate cellular differentiation. They then used gene transfer technology to insert the three genes into mature amniotic cells in mouse models, then shut one of them off after a brief period of activity by using a special molecular inhibitor.
Remarkably, 20 percent of the amniotic cells could efficiently be reprogrammed into endothelial cells, says Ginsburg, and better yet, "these transcription factors do not cause cancer. The cells are not tumorigenic and could in the future be infused into patients with a large margin of safety."
Next, the Cornell team will examine whether other transcription factors could be used to reprogram the amniotic cells into many other tissue-specific cells, such as those that make up muscles, the brain, pancreatic islet cells and other parts of the body.
"While our work focused primarily on the reprogramming of amniotic cells into endothelial cells, we surmise that through the use of other transcription factors and growth conditions, our group and others will be able to reprogram mouse and human amniotic cells virtually into every organ cell type, such as hepatocytes in the liver, cardiomyocytes in heart muscle, neurons in the brain and even chondrocytes in cartilage, just to name a few," Ginsberg says.
A patent has been filed on the discovery.
"The idea of a platform using amniotic cells can be very lucrative," says Ginsburg. "We would love to share our discovery with the world and have other people follow our lead and start doing studies with these cells, showing that they can be a successful source of regenerative therapy."
In a news release describing the study, co-author Dr. Zev Rosenwaks, the Revlon Distinguished Professor of Reproductive Medicine in Obstetrics and Gynecology at Cornell, said the implications of these findings "would be enormous in the field of translational regenerative medicine."
"The greatest obstacle to overcome in the pursuit to regenerate specific tissues and organs is the requirement for substantial levels of cells—in the billions—that are stable, safe and durable. Our approach will bring us closer to this milestone," stated Rosenwaks.
The study, "Efficient Direct Reprogramming of Mature Amniotic Cells into Endothelial Cells by ETS Factors and TGFb Suppression," was supported by the Howard Hughes Medical Institute; the Ansary Stem Cell Institute; the Qatar National Priorities Research Foundation; the Qatar Foundation BioMedical Research Program; the Empire State Stem Cell Board; the New York State Department of Health; and the National Institutes of Health Heart, Lung and Blood Institute. Other co-authors credited on the study included Bi-Sen Ding; Daniel Nolan; Fuqiang Geng; Jason M. Butler; William Schachterle; Susan Mathew; Stephen T. Chasen; Jenny Xiang; Koji Shido; and Dr. Olivier Elemento.