Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Same disease, different stem cell models

07.05.2010
Fragile X syndrome iPS cells and embryonic stem cells behave differently

In the last three years, a new technique for reprogramming adult cells has given scientists an easier and less controversial way to harness the power of embryonic-like stem cells to study human disease from its earliest beginnings in hopes of gleaning new insights into the root causes of disease and developing new therapies.

But the reprogrammed cells, known as induced pluripotent stem (iPS) cells, are different from embryonic stem cells in their ability to model a human genetic disease, a new cell-to-cell comparison shows.

"This is the first example where we can clearly show induced pluripotent stem cells and embryonic stem cells behave differently in a disease model," said co-senior author George Daley, Director of the Stem Cell Transplantation Program at Children’s Hospital Boston. Daley's team has turned patient cells back into stem cells for a range of diseases.

In the new study in the May 7 Cell Stem Cell, the researchers made iPS cells from the skin cells of three patients with fragile X syndrome, the most common form of inherited mental retardation in boys. By almost every measure, virtually the entire genome was dialed back in time. The key exception was the disease-causing gene, which becomes inactivated to cause the disease, and did not get turned back on in the iPS cells.

"Both iPS and embryonic stem cell lines have the same mutation," said co-senior author Nissim Benvenisty, director of the Stem Cell Unit at the Hebrew University of Jerusalem, whose lab established an embryonic stem cell model of fragile X syndrome three years ago at a time when such research was severely restricted in the United States. "However, we saw a difference between the two systems."

About one-third of children with fragile X have behavioral symptoms that overlap with autism. Scientists hope a stem cell model of fragile X will help them study what goes wrong and test drugs that may help treat both abnormal conditions.

"It’s known that the fragile X protein regulates the expression of receptors at the synapse between nerve cells," Daley said. "In the absence of the protein, nerve cells express too much of an excitatory receptor."

The mutation that silences the fragile X gene and blocks its protein lies buried just upstream of the gene's coding region in triplet repeats of DNA. Normally, that region harbors up to 50 CGG repeats. Fragile X syndrome occurs when the repeats number more than 200.

The mutation alone is not enough to cause disease. "In rare cases, people can have the full mutation, but the gene is still expressed," said co-first author Achia Urbach, a postdoctoral fellow in the Daley lab at Children's and former graduate student in the Benvenisty lab in Jerusalem.

Three years ago, Urbach, Benvenisty and their Israeli collaborators reported the first direct evidence that the fragile X gene was silenced upon differentiation. The fragile X gene, called FMR1, remains active until cells begin to differentiate in preparation for forming different tissues and organs. Somehow, that process locks down the DNA with epigenetic changes that prevent the gene from being transcribed. To study the FMR1 gene silencing in embryonic stem cells, they established embryos affected by the fragile X condition in collaboration with Lis Maternity Hospital in Tel Aviv. The affected embryos were identified by preimplantation diagnosis, resulting from IVF treatment of a woman who carried the fragile X mutation and wanted healthy babies, Urbach said.

After that paper, Urbach joined the Daley lab to study iPS cells. Beginning with patients' cells, Daley's group has developed more than a dozen disease-specific stem cell lines. "We thought it would be interesting to compare the two systems," said Urbach of the embryonic and induced fragile X stem cells.

Urbach and co-first author Ori Bar-Nur, a graduate student in Benvenisty's lab first created fragile X iPS cells from the skin cells of two affected patients and related lung cells from a 22-week-old fetus with fragile X, testing them extensively to assure themselves and other researchers of their stem-cell qualities. They also investigated why the FMR1 gene remained stubbornly locked down.

"We show the reason the gene is not expressed is because it still has the epigenetic markers for silencing," Urbach said.

The fragile X gene may be one of the first genes to resist the reprogramming process that transforms adult tissue cells into iPS cells, but it's likely not the last, said the researchers.

"This raises a general caution for using iPS as a faithful reflection of a disease process," Daley said. "There are lots of conditions where you have gene defects that lead to gene silencing. Such conditions may not be faithfully modeled by iPS cells. Fragile X is a disease where using embryonic stem cells as a tool is essential."


The differences in the iPS and embryonic fragile X stem cells make them useful for different types of studies, the researchers say. "On one hand, iPS cells are not as good for modeling the inactivation of the gene," Benvenisty said. "On the other hand, they may be a better model for studying neurons lacking expression of the gene."

"New insights into fragile X have stimulated clinical trials of drugs that block the overactive excitatory receptors in nerve cells," Daley said. "Early results hint that these drugs might ameliorate the condition of fragile X. With our stem cell models-diseases in a dish, if you will-we can test whether the drugs will reverse abnormal connections at the synapses that we think are at the basis of this condition. If your goal is blocking FMR1 gene silencing, you're better off working on drug screens in embryonic stem cells than in iPS cells."

CITATION: "Differential modeling of Fragile X syndrome by human embryonic stem cells and induced-pluripotent stem cells," Achia Urbach1*, Ori Bar-Nur2*, George Q. Daley1# and Nissim Benvenisty2# 1. Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Harvard Stem Cell Institute, Boston, MA 02115, USA. 2. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.

FUNDING: EMBO, Israel Science Foundation, European Community, Legacy Heritage Fund of New York, National Institutes of Health, Howard Hughes Medical Foundation, Manton Center for Orphan Disease Research.


Contact:
Bess Andrews
617-919-3110
elizabeth.andrews @childrens.harvard.edu
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.

Bess Andrews | EurekAlert!
Further information:
http://www.childrenshospital.org/newsroom

More articles from Life Sciences:

nachricht MicroRNA helps cancer evade immune system
19.09.2017 | Salk Institute

nachricht Ruby: Jacobs University scientists are collaborating in the development of a new type of chocolate
18.09.2017 | Jacobs University Bremen gGmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

Im Focus: Artificial Enzymes for Hydrogen Conversion

Scientists from the MPI for Chemical Energy Conversion report in the first issue of the new journal JOULE.

Cell Press has just released the first issue of Joule, a new journal dedicated to sustainable energy research. In this issue James Birrell, Olaf Rüdiger,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

New quantum phenomena in graphene superlattices

19.09.2017 | Physics and Astronomy

A simple additive to improve film quality

19.09.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>