The study, published Oct. 18 in the journal Cell, presents an exciting newalternative to the controversial use of human embryonic stem cells (hESCs) andsome of the proliferation or safety issues encountered when using them or othertypes of cells.
"Some of the controversy and problems we have with stem cellresearch 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 ofpossibly improving the techniques used in the endeavor of regenerativemedicine."
Previous attempts to clinically produce endothelial cellsthat can be used to treat patients have failed because isolation of these cellsfrom adult organs is inefficient. Scientists have fared no better by attemptingto produce cells from the body's master pluripotent stem cells. Experimentsusing these cells, which can become any cell in the body, did in fact produceendothelial cells—but they often grew poorly, could not be fully differentiatedor even caused tumor growth.
That isn't the case with the cells used in the Cornellstudy, Ginsburg quickly notes. The cells were collected during routinemid-pregnancy amniocentesis procedures with the permission of the expectantmother. Ginsburg stresses that these cells are not embryonic.
"These are mostly cells sloughed off the fetus. They arefloating 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 cantake these cells out and grow them in culture like any other cell type."
And that is precisely what the research team did, turning tohuman amniotic fluid-derived cells, which some studies had suggested have thepotential to become differentiated cell types—if stimulated in the right way.
"We showed that we can start with 100,000 amniotic cells andwithin four to five weeks, produce 6.5 billion cells," says Ginsburg.
The researchers looked for the genes that hESCs use todifferentiate into endothelial cells, identifying three genes that are expressedduring vascular development: members of the "E-Twenty-Six" (ETS) family oftranscription factors known to regulate cellular differentiation. They thenused gene transfer technology to insert the three genes into mature amnioticcells in mouse models, then shut one of them off after a brief period ofactivity by using a special molecular inhibitor.
Remarkably, 20 percent of the amniotic cells couldefficiently be reprogrammed into endothelial cells, says Ginsburg, and betteryet, "these transcription factors do not cause cancer. The cells are nottumorigenic and could in the future be infused into patients with a largemargin of safety."
Next, the Cornell team will examine whether othertranscription factors could be used to reprogram the amniotic cells into manyother 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 ofamniotic cells into endothelial cells, we surmise that through the use of othertranscription factors and growth conditions, our group and others will be ableto reprogram mouse and human amniotic cells virtually into every organ celltype, such as hepatocytes in the liver, cardiomyocytes in heart muscle, neuronsin the brain and even chondrocytes in cartilage, just to name a few," Ginsbergsays.
A patent has been filed on the discovery.
"The idea of a platform using amniotic cells can be verylucrative," says Ginsburg. "We would love to share our discovery with the worldand 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. ZevRosenwaks, the Revlon Distinguished Professor of Reproductive Medicine inObstetrics 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 regeneratespecific tissues and organs is the requirement for substantial levels ofcells—in the billions—that are stable, safe and durable. Our approach willbring us closer to this milestone," stated Rosenwaks.
The study, "Efficient Direct Reprogramming of MatureAmniotic Cells into Endothelial Cells by ETS Factors and TGFb Suppression," wassupported by the Howard Hughes Medical Institute; the Ansary Stem CellInstitute; the Qatar National Priorities Research Foundation; the QatarFoundation BioMedical Research Program; the Empire State Stem Cell Board; the NewYork State Department of Health; and the National Institutes of Health Heart,Lung and Blood Institute. Other co-authors credited on the study includedBi-Sen Ding; Daniel Nolan; Fuqiang Geng; Jason M. Butler; William Schachterle;Susan Mathew; Stephen T. Chasen; Jenny Xiang; Koji Shido; and Dr. OlivierElemento.
