Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene silencing may be responsible for induced pluripotent stem cells' limitations

26.04.2010
Better understanding of mechanisms involved should improve reprogramming of embryonic-like cells

Scientists may be one step closer to being able to generate any type of cells and tissues from a patient's own cells. In a study that will appear in the journal Nature and is receiving early online release, investigators from the Massachusetts General Hospital Center for Regenerative Medicine (MGH-CRM) and the Harvard Stem Cell Institute (HSCI), describe finding that an important cluster of genes is inactivated in induced pluripotent stem cells (iPSCs) that do not have the full development potential of embryonic stem cells. Generated from adult cells, iPSCs have many characteristics of embryonic stem cells but also have had significant limitations.

"We found that a segment of chromosome 12 containing genes important for fetal development was abnormally shut off in most iPSCs," says Konrad Hochedlinger, PhD, of the MGH-CRM and HSCI, who led the study. "These findings indicate we need to keep improving the way we produce iPSCs and suggest the need for new reprogramming strategies."

Although iPSCs appear quite similar to embryonic stem cells and give rise to many different types of cells, they have important limitations. Several molecular differences have been observed, particularly in the epigenetic processes that control which genes are expressed, and procedures that are able to generate live animals from the embryonic stem cells of mice are much less successful with iPSCs.

Previous studies have compared iPSCs generated with the help of viruses, which can alter cellular DNA, to embryonic stem cells from unrelated animals. To reduce the chance that the different sources of the cells were responsible for observed molecular differences, the MGH/HSCI research team prepared two genetically matched cell lines. After generating mice from embryonic stem cells, they used a technique that does not use viruses to prepare lines of iPSCs from several types of cells taken from those animals. They then compared the iPSCs with the original, genetically identical embryonic stem cells.

The most stringent assay of cells' developmental potential showed that two tested lines of embryonic stem cells were able to generate live mice as successfully as in previous studies, but no animals could be generated from genetically matched iPSCs. Closely comparing RNA transcription profiles of several matched cell lines revealed significantly reduced transcription of two genes in the iPSCs. Both genes are part of a gene cluster on chromosome 12 that normally is maternally imprinted – meaning that only the gene copies inherited from the mother are expressed.

Examination of more than 60 iPSCs lines developed from several types of cells revealed that this gene cluster was silenced in the vast majority of cell lines. While the gene-silenced iPSCs were able to generate many types of mouse tissues, their overall developmental potential was limited. In an assay that produces chimeric animals that incorporate cells from two different stem cells, mice produced from gene-silenced cells had very few tissues that originated from the iPSCs. However, in a few iPSC lines the gene cluster was normally activated, and in the most rigorous developmental assay, those iPSCs were as successful in producing live animals as embryonic stem cells have been. The authors believe this is the first report of animals being produced entirely from adult-derived iPSCs.

"The activation status of this imprinted cluster allowed us to prospectively identify iPSCs that have the full developmental potential of embryonic stem cells," says Matthias Stadtfeld, PhD, of the MGH-CRM and HSCI, a co-lead author of the report. "Identifying pluripotent cells of the highest quality is crucial to the development of therapeutic applications, so we can ensure that any transplanted cells function as well as normal cells. It's going to be important to see whether iPSCs derived from human patients have similar differences in gene expression and if they can be as good as embryonic stem cells – which continue to be the gold standard – in giving rise to the 220 functional cell types in the human body."

Hochedlinger adds, "Previous studies in mice have shown that embryonic stem cells derived from nuclear transfer – the technique used to clone animals – are indistinguishable from stem cells derived from fertilized embryos. Nuclear transfer is another way of reprogramming adult cells into embryonic-like cells, and comparing that approach with iPSC generation may yield important insights into ways of producing the safest and highest quality pluripotent cells for use in patients." Hochedlinger is an associate professor in the Harvard University Department of Stem Cell and Regenerative Medicine.

Efie Apostolou, PhD, of the MGH-CRM and HSCI is also a co-lead author of the Nature report. Additional co-authors are Patricia Follett, MGH-CRM and HSCI; Toshi Shioda, MD, PhD, MGH Cancer Center; Hidenori Akutsu, MD, National Institute for Child Health and Development; Sridaran Natesan, PhD, Sanofi-Aventis and Atsushi Fukuda and Tomohiro Kono, PhD, Tokyo University of Agriculture. Hochedlinger is a Howard Hughes Medical Institute Early Career Scientist and received a Director's Innovator Award from the National Institute of Health. Additional support for the study includes grants from the Schering Foundation, the Jane Coffin Childs Memorial Fund and Sanofi-Aventis.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Sue McGreevey | EurekAlert!
Further information:
http://www.mgh.harvard.edu/

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>