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October 19, 2012--------News Archive Return to: News Alerts

Mid-gestation amniotic fluid cells can become new endothelial cells,
through the
addition of 3 ETS genes, thereby becomming available for vascular repair.


A new blood vessel composed of new endothelial cells,
created from reprogrammed amniotic fluid-derived cells

WHO Child Growth Charts

       

Reprogrammed Amniotic Fluid Cells Could Treat Vascular Diseases

Researchers have discovered an approach for converting amniotic fluid cells into endothelial cells in order to repair damaged blood vessels in heart disease, stroke, diabetes and trauma

A research team at Weill Cornell Medical College has discovered a way to utilize diagnostic prenatal amniocentesis cells, reprogramming them into abundant and stable endothelial cells capable of regenerating damaged blood vessels and repairing injured organs.

Their study, published online today in Cell.


The study paints a picture of a future therapy where
amniotic fluid, now collected from thousands of
amniocentesis procedures yearly in mid-pregnancy
for the purpose of examining fetal chromosomes,
would be collected with the permission
of women undergoing the procedure.

These cells, which are not embryonic,
would then be treated with a trio of genes
that reprogram them quickly into billions
of endothelial cells – the cells that line
the entire circulatory system.

The new endothelial cells could be frozen
and banked the same way blood is currently,
and patients in need of blood vessel repair
would be able to receive the cells
through a simple injection.


If proven in future studies, this novel therapy could dramatically improve treatment for disorders linked to a damaged vascular system, including heart disease, stroke, lung diseases such as emphysema, diabetes, and trauma, says the study's senior investigator, Dr. Shahin Rafii, the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell Medical College and co-director of its Ansary Stem Cell Institute.


"Currently, there is no curative treatment available
for patients with vascular diseases, and the common
denominator to all these disorders is dysfunction of
blood vessels, specifically endothelial cells that are
the building blocks of the vessels,"

Dr. Shahin Rafii
Howard Hughes Medical Institute investigator

But these cells do much more than just provide
the plumbing to move blood. Dr. Rafii has recently
led a series of transformative studies showing
endothelial cells in blood vessels produce growth
factors that actively participate in organ maintenance,
repair and regeneration.

So while damaged vessels cannot repair the organs
they nurture with blood, he believes an infusion
of new endothelial cells could.

"Replacement of the dysfunctional endothelial cells
with transplanted, normal, properly engineered
cultured endothelial cells could potentially
provide for a novel therapy for many patients.

In order to engineer tissues with clinically relevant
dimensions, endothelial cells can be assembled
into porous three-dimensional scaffolds that,
once introduced into a patient's injured organ,
could form true blood vessels."

Dr. Sina Rabbany
study co-author, adjunct associate professor
bioengineering, Genetic Medicine, Weill Cornell


Dr. Rafii says that this study will potentially create a new field of translational vascular medicine. He estimates that as few as four years are needed for the preclinical work to seek FDA approval to start human clinical trials to advance the potential of reprogrammed endothelial cells for treatment of vascular disorders.

As part of their study, the research team proved, in mice, that endothelial cells reprogrammed from human amniotic cells could engraft into an injured liver to form stable, normal and functional blood vessels.

"We have shown that these engrafted endothelial cells have the capacity to produce unique growth factors to promote regeneration of the liver cells," says the study's lead investigator, Dr. Michael Ginsberg, a senior postdoctoral associate in Dr. Rafii's laboratory.

"The novelty of this technique is that, from 100,000 amniotic cells -- a small amount -- we grew more than six billion new authentic endothelial cells within a matter of weeks," Dr. Ginsberg says. "And when we injected these cells into mice, a substantial amount of them engrafted into regenerating vessels. It was remarkable to see that these cells went right to work building new blood vessels in the liver as well as producing the right growth factors that could potentially regenerate and repair injured organs."

The Goldilocks of Cellular Reprogramming

To date, there have been many failed attempts to clinically produce endothelial cells that can be used to treat patients. Isolation of endothelial cells from adult organs so they can be grown in the laboratory is not efficient, according to Dr. Daylon James, study co-author and an assistant professor of stem cell biology in reproductive medicine at Weill Cornell Medical College.

Attempts to produce the cells from the body's master pluripotent stem cells have also not worked out. Experiments have shown that prototypical pluripotent stem cells, such as embryonic stem cells, which have the potential to become any cell in the body, produce endothelial cells but often grow poorly, and if not fully differentiated could potentially cause cancer.

"Coaxing adult cells to revert to a stem-like state so they can then be pushed to form endothelial cells is, at this point, not clinically feasible, and ongoing studies in my lab are focused on achieving this goal," says Dr. James, who is also assistant professor of stem cell biology in obstetrics and gynecology and genetic medicine at Weill Cornell.

Therefore, Dr. Rafii's team searched for a new source of cells that they could turn into a vast supply of stable endothelial cells. They probed human amniotic fluid-derived cells, which some studies had suggested have the potential to become differentiated cell types, if stimulated in the right way -- which no one had yet identified.

In their first experiments with these cells three years ago, Dr. Ginsberg used cells taken from an amniocentesis given at 16 weeks of gestation. Researchers found that amniotic cells are the "Goldilocks" of cellular programming. "They are not as plastic and unstable as endothelial cells derived from embryonic cells or as stubborn as those produced from reprogramming differentiated adult cells," Dr. Ginsberg says. Instead, he says amniotic cells provide conditions that are just right – the so-called "Goldilocks Principle" – for producing endothelial cells.


In order to make that discovery, researchers had to know
how to reprogram amniotic cells. To this end,
they looked for genes that embryonic stem cells
use to differentiate into endothelial cells.

Dr. Rafii's group identified three genes
expressed during vascular development,
all of which are members of the E-twenty six
(ETS) family of transcription factors known
to regulate cellular differentiation,
especially blood vessel formation.

Next, they used gene transfer technology
to insert the three genes into mature amniotic cells,
then shut one of them off after a brief and critical
period of activity using a special molecular inhibitor.
Remarkably, 20 percent of the amniotic cells could
efficiently be reprogrammed into endothelial cells.

"This is quite an achievement since current strategies
to reprogram adult cells result in less than one percent
successful reprogramming into endothelial cells."


Dr. Shahin Rafii


"These transcription factors do not cause cancer,
and the endothelial cells reprogrammed from
human amniotic cells are not tumorigenic and
could in the future be infused into patients
with a large margin of safety,"

Dr. Ginsberg

The findings suggest that other transcription factors
could be used to reprogram 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," Dr. Ginsberg says.

"Obviously, the implications of these findings would be enormous in the field of translational regenerative medicine," emphasizes study co-author Dr. Zev Rosenwaks, the Revlon Distinguished Professor of Reproductive Medicine in Obstetrics and Gynecology at Weill Cornell Medical College and director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Dr. Rosenwaks: "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."

"Most importantly, these endothelial cells could be reprogrammed from amniotic cells from genetically diverse individuals," says co-author Dr. Venkat R. Pulijaal, director of the Cytogenetic Laboratory, associate professor of clinical pathology and laboratory medicine at Weill Cornell. What endothelial cells a patient receives would depend on their human leukocyte antigen (HLA) type, which is a set of self-recognition molecules that enable doctors to match a patient with potential donors of blood or tissue.

"Selecting the proper immunologically matched endothelial cells for each patient would be akin to blood typing. There are only so many varieties, which are well represented across the amniotic fluid cells that could be obtained, frozen and banked from wide variety of ethnic groups around the world," Dr. Rafii says.


A patent has been filed on this discovery.


Other study co-authors from Weill Cornell Medical College include: Dr. Bi-Sen Ding, Dr. Daniel Nolan, Dr. Fuqiang Geng, Dr. Jason M. Butler, Dr. William Schachterle, Dr. Susan Mathew, Dr. Stephen T. Chasen, Dr. Jenny Xiang, Dr. Koji Shido and Dr. Olivier Elemento.

Dr. Rafii's research is funded by the Howard Hughes Medical Institute, the National Heart, Lung, and Blood Institute, the Ansary Stem Cell Institute at Weill Cornell Medical College, the Empire State Stem Cell Board and New York State Department of Health grants, and the Qatar National Priorities Research Foundation.

Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies.

In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient.

Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

Original article: http://weill.cornell.edu/news/releases/wcmc/wcmc_2012/10_19_12.shtml