Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Memory loss enables the production of stem cells

10.12.2015

In a study published in this week’s edition of NATURE, scientists from the Research Institutes of Molecular Biotechnology (IMBA) and Molecular Pathology (IMP) in Vienna and from the Harvard Medical School in Boston have identified a long-sought “roadblock factor” in stem cell engineering that prevents the conversion of adult cells into induced pluripotent stem cells. By suppressing this factor, the team discovered a way to erase the memory of cells, which makes it much easier to convert any cell into a stem cell.

Stem cells have the potential to develop into any specialized cell type, which makes them a valuable resource in research and regenerative medicine. Since such pluripotent cells can usually be only found in embryonic tissue prior to implantation, their isolation raises ethical concerns.


The CAF-1 complex preserves the identity of cells. Suppression of CAF-1 erases the memory of cells and makes them susceptible to reprogramming into pluripotent stem cells.

IMP-IMBA

In 1996, Dolly the sheep proved that genetic information from mature somatic cells can be used to generate pluripotent stem cells that in turn develop into an entire animal. In 2006, the Japanese physician Shinya Yamanaka discovered that somatic cells can be directly “reprogrammed” into a pluripotent state using four stem cell factors. The ability to create these induced pluripotent stem cells (iPS cells) revolutionized stem cell biology and was awarded the Nobel Prize in 2012.

The search for a roadblock-factor

While iPS cells are a powerful resource for biomedical research and tissue engineering, their production typically involves slow and inefficient protocols, which remains a major limitation of this technology. As a possible solution to this problem, researchers have long thought of so-called “roadblock-factors” that prevent the conversion from normal tissue into pluripotent stem cells. However, the precise factors forming this roadblock and their mechanism of action so far are poorly understood.

To search for the missing factor(s), scientists at the Vienna Biocenter (VBC) and Harvard University sought to employ newly developed genetic screening methods. In early 2014, they formed a research team combining unique expertise and experimental reagents: Ulrich Elling and Josef Penninger at IMBA are experts in high-throughput genetic screens and stem cell biology; Johannes Zuber from the IMP has led several successful cancer screens using genetic libraries his team has developed at the VBC; and Konrad Hochedlinger from Harvard University is a world leader in iPS cell reprogramming and, together with his postdoc Sihem Cheloufi, has established unique reagents and assays to study this process.

Cells don’t forget where they come from

As prime candidates in the search for roadblock-factors, the team decided to focus on so-called chromatin regulators - genes that control the packaging and bookmarking of DNA, which is known to underlie the “epigenetic memory” of a cell.

“Cells have a certain level of memory,” explains Johannes Zuber. “For example, a skin cell knows it is a skin cell, even after Yamanaka factors have been introduced. We wanted to find out which chromatin factors stabilize this memory and which mechanism prevents iPS cells from forming.” To answer this question, the team established a genetic library targeting 615 known chromatin regulators, and designed a sophisticated screening approach that allowed to test each of these factors.

The results of this screen were striking: Among 615 genes, four factors clearly stood out as top hits. Of those, only one had previously been described as a candidate roadblock. The new hits include CHAF1A and CHAF1B, forming the CAF-1-complex (chromatin assembly factor 1), and UBE2I (ubiquitin-conjugating enzyme E2I).

When the researchers thoroughly tested these genes, the effects were stunning: While inhibiting previously described roadblock-genes increases iPSC reprogramming three- to fourfold, losing CAF-1 or UBE2I made this process 50- to 200-fold more efficient. Moreover, in the absence of CAF-1, reprogramming turned out to be much faster: While the process normally takes about nine days, the researchers in Vienna could detect the first iPS cells already after four days.

A long-awaited breakthrough

“The CAF-1 complex ensures that during DNA replication and cell division daughter cells keep their epigenetic memory, which is encoded on the histones that the DNA is wrapped around,” explains Ulrich Elling. “When we block CAF-1, daughter cells fail to wrap their DNA the same way, lose this information, and convert into blank sheets of paper. In this state, they respond more sensitively to signals from the outside, meaning we can manipulate them much more easily.”

In finding CAF-1, the researchers identified a complex that allows cell memory to be erased and rewritten, which is a long-awaited breakthrough for stem cell research. In their study, the team demonstrated how suppression of the CAF-1-complex turns the slow and inefficient production of iPS cells into a straight-forward method.

But the significance of this discovery probably goes beyond this important application. The authors speculate that CAF-1 may provide a general key to facilitate the “reprogramming” of cells in scenarios such as tissue damage and disease. As Josef Penninger puts it: “The best-case scenario is that with this insight, we hold a universal key in our hands that will allow us to model cells at will.”


Original Publication
The paper “The histone chaperone CAF-1 safeguards somatic cell identity” by Cheloufi & Elling et al. will be published in Nature on December 10, 2015.

About IMP
The Research Institute of Molecular Pathology (IMP) in Vienna is a basic biomedical research institute largely sponsored by Boehringer Ingelheim. With over 200 scientists from 35 nations, the IMP is committed to scientific discovery of fundamental molecular and cellular mechanisms underlying complex biological phenomena. Research areas include cell and molecular biology, neurobiology, disease mechanisms and computational biology. The IMP is located at the Vienna Biocenter.

About IMBA
The Institute of Molecular Biotechnology (IMBA) is a research institute that conducts basic research in molecular biology. It was founded in 1999 as a 100% subsidiary of the Austrian Academy of Sciences (ÖAW) in the legal form of a limited liability company. Today it is the largest Institute of the ÖAW.In 13 interdisciplinary groups, the researchers at IMBA focus on stem cell biology and investigate cellular processes like RNA interference, cell division and epigenetics. Potential fields of application include major disease areas such as inflammation, autoimmune disorders, cardiovascular and neurodegenerative diseases, and cancer.


Media Contact at the IMP
Dr. Heidemarie Hurtl
IMP Communications
hurtl@imp.ac.at
+43 (0)1 79730 3625

Media Contact at IMBA
Dr. Sophie Hanak, M.sc.
IMBA Communications
sophie.hanak@imba.oeaw.ac.at
+43 (0) 1 79044 3628

Dr. Heidemarie Hurtl | idw - Informationsdienst Wissenschaft
Further information:
http://www.imp.ac.at

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>