Stanford study finds IPS cells match embryonic stem cells in modeling human disease

December 19, 2011

STANFORD, Calif. -- Stanford University School of Medicine investigators have shown that iPS cells, viewed as a possible alternative to human embryonic stem cells, can mirror the defining defects of a genetic condition -- in this instance, Marfan syndrome -- as well as embryonic stem cells can. An immediate implication is that iPS cells could be used to examine the molecular aspects of Marfan on a personalized basis. Embryonic stem cells, on the other hand, can't do this because their genetic contents are those of the donated embryo, not the patient's.

This proof-of-principle regarding the utility of induced pluripotent stem cells also has more universal significance, as it advances the credibility of an exciting approach that's been wildly acclaimed by some and viewed through gimlet eyes by others: the prospect of using iPS cells in modeling a broad range of human diseases. These cells, unlike ESCs, are easily obtained from virtually anyone and harbor a genetic background identical to the patient from which they were derived. Moreover, they carry none of the ethical controversy associated with the necessity of destroying embryos.

"Our in vitro findings strongly point to the underlying mechanisms that may explain the clinical manifestations of Marfan syndrome," said Michael Longaker, MD, professor of surgery and senior author of the study, which will be published online Dec. 12 in Proceedings of the National Academy of Sciences. Longaker is the Dean P. and Louise Mitchell Professor in the School of Medicine and co-director of the school's Institute for Stem Cell Biology and Regenerative Medicine. The study's first author is Natalina Quarto, PhD, a senior research scientist in Longaker's laboratory.

Marfan syndrome is an inherited connective-tissue disorder that occurs in one in 10,000 to one in 20,000 individuals. It is caused by any of a large number of defects in one gene. People with this condition tend to be very tall and thin and to suffer from osteopenia, or poor bone mineralization. Medical experts speculate that Abraham Lincoln, for example, suffered from this disorder. Marfan can also profoundly affect the eyes and cardiovascular system.

In this study, both iPS cells and embryonic stem cells carrying a mutation that causes Marfan syndrome showed impaired ability to form bone, and all too readily formed cartilage. These aberrations mirror the most prominent clinical manifestation of the disease.

Discovered in 2006, induced pluripotent stem cells, or iPS cells, are derived from fully differentiated tissues such as the skin. Yet they harbor the same capacity of embryonic stem cells to differentiate into all the tissues of the body as well as to replicate for indefinite periods in a dish. Because they offer an ethically uncomplicated alternative to embryonic stem cells, iPS cells have fueled the hope that they can replace ESCs in scientists' efforts to analyze, in a dish, the cellular defects ultimately responsible for diseases ranging from diabetes to Parkinson's and even such complex conditions as cardiovascular disease and autism.

One hope for iPS cells is to be able to differentiate them in a dish into tissues of interest -- say, nerve cells of a patient with Parkinson's or autism -- and study these resulting cells' characteristics with an eye to understanding the disease in a patient-specific way. This would be impossible to do with embryonic stem cells, unless ESCs from donated human eggs could be modified through the so-far insurmountable feat of substituting a patient's own genetic material into these eggs to reflect the patient's own genetic background.

While scientists have set the goal of using these cells for more than research purposes -- developing therapeutic applications in regenerative medicine -- that prospect is more distant. Scientists will have to develop the capacity first to repair within such cells, whether iPS or ESC, the genetic defects determined to be responsible for a patient's condition, and then differentiate the cells in bulk into the affected tissue, which could be used for regenerative medicine. Again, iPS cells in theory might be a better bet because, being initially derived from a particular patient, they could differentiate into tissues that are less likely to provoke graft rejection than similar tissues produced using a donor embryo's ESCs.

However, a number of studies have reported subtle differences between iPS cells and ESCs, implying that the two may not be equivalent. Experts have wondered whether these differences may render iPS cells inadequate substitutes for ESCs in modeling disease states. This study suggests otherwise, Longaker said.

The opportunity for a head-to-head comparison of ESCs and iPS cells arose serendipitously when Barry Behr, PhD, professor of obstetrics and gynecology and director of the Stanford Fertility & Reproductive Medicine Center, performed pre-implantation genetic diagnosis to select embryos for in vitro fertilization. Behr and Renee Reijo-Pera, PhD, professor of obstetrics and gynecology and director of the Stanford Center for Reproductive and Stem Cell Biology, discovered that one candidate embryo carried a genetic mutation that causes Marfan syndrome. This embryo was thus not deemed fit for implantation. But it was a potential source of embryonic stem cells, each of which would carry the Marfan-causing mutation. So, rather than discarding or storing it, the researchers received permission to derive the embryonic stem cells Longaker's team studied. (Both Behr and Reijo-Pera are co-authors of the study.)

What followed was a collaboration featuring an all-star cast that included senior faculty members from several departments in the medical school as well as researchers at the University of Naples Federico II in Italy. The researchers generated ESCs from the Marfan-carrying embryo. They also obtained skin biopsies from Marfan patients from another Stanford co-author, Uta Francke, MD, professor of genetics and of pediatrics, and used cells called fibroblasts from these samples to derive iPS cells by means of what have now become routine procedures.

"Here we had both iPS cells and embryonic stem cells side by side in culture dishes, both containing the defective gene responsible for Marfan. This was a perfect opportunity to compare them head to head," Longaker said.

When they did that, Longaker, Quarto and their associates found that both the iPS cells derived from the skin of Marfan patients and the ESCs from the embryonic Marfan carrier exhibited aberrations identical to those that characterize the disorder's observed skeletal symptoms -- a diminished capacity to form bone and a heightened propensity for forming cartilage instead.

The scientists began the study with the knowledge that mutations causing Marfan syndrome are found in a gene that codes for a protein called FIBRILLIN-1. Importantly, FIBRILLIN-1 is known, in turn, to inhibit the activity of an intercellular signaling molecule named TGF-beta. Mouse studies have indicated that the absence or mutation of FIBRILLIN-1 results in a failure of this inhibition. This study showed for the first time in humans that the reason for stem cells' failure to form bone and overzealous conversion to cartilage directly resulted from their consequent exposure to more, and more-activated, TGF-beta than normal people's cells are.

The success of iPS cells in faithfully reproducing Marfan's cellular and molecular defects every bit as well as ESCs do may allow the disease to be studied (and, in the long run, even treated) in a case-by-case manner. While Marfan is a single-gene disorder, it can and does result from any of a large number of mutations to that one gene -- upward of 600 have been identified so far --which manifest as a spectrum of subtle differences in symptoms from one patient to the next.
The study was funded largely by a grant from the California Institute for Regenerative Medicine, with additional funding from the National Institutes of Health. Other co-authors were Eric Chiao, PhD, co-senior author of the study and a former instructor of obstetrics and gynecology who is now at the pharmaceutical company Roche; Brian Leonard, formerly a research assistant in the Chiao and Reijo-Pera labs; Shuli Li, MD, PhD, a research associate in Longaker's lab; and former postdoctoral researcher Melanie Marchand, PhD, and research assistant Erica Anderson, both in the Chiao, Reijo-Pera and Longaker labs.

Information about the medical school's departments of Surgery, of Pediatrics and of Obstetrics and Gynecology, which also supported the work, is available at, and, respectively.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit

Stanford University Medical Center

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to