Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers in Berlin and Bath Identify “Naïve-Like” Human Stem Cells

16.10.2014

In their search for the earliest possible stage of development of human embryonic stem cells (hESCs) that still have the potential to develop into any types of body cells and tissue, researchers from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, and the University of Bath, United Kingdom, have apparently been successful. Jichang Wang, Gangcai Xie, and Dr. Zsuzsanna Izsvák (MDC), together with Professor Laurence D. Hurst (University of Bath), report the discovery of a subtype of cells in culture dishes with hESCs and human induced pluripotent stem cells (hiPSCs) that resemble this very early, pluripotent or naïve state (Nature, doi:10.1038/nature13804)*.

They also discovered the mechanism that turns human ES cells into naïve-like human stem cells. While this has potential implications for medicine and for understanding early human development, an evolutionary enigma still remains unsolved.


Newly discovered naïve-like human stem cells (green) in a culture dish with human embryonic stem cells.

(Photo: Jichang Wang/ Copyright: MDC)

Human embryonic stem cells (hESCs) differ considerably from those of mice. Mouse naïve cultures resemble the inner cell mass which gives rise to the embryo, while none of the cultured hESC lines do. “Naïve” ESCs of mice are easy to maintain, but not human ESCs isolated from pre-implantation embryos. The hESC lines, researchers work with in their laboratories are considered to be less naïve, and have limited differentiation potential. Researchers hypothesize that they have partially lost their pluripotency. Why this is so remains unclear.

What properties characterize human naïve stem cells? Can they be identified and proliferated in the laboratory and retained in culture? Researchers in Europe, Asia and the USA are trying to find the answers to these questions in order to be able to use these cells for therapy in the future.

Evolution pointed the way

It was evolution that showed the researchers in Bath and Berlin the way to the successful approach. They pinpointed one particular class of ancient viruses called HERVH (human endogenous retrovirus H). HERVH integrated into our DNA millions of years ago, and although it does not function as a virus any longer, it is not silent.

HERVH-derived sequences appear at a very early stage in human embryos, that is, HERVH is highly expressed at just the right time and place in human embryos where one would expect to see naïve stem cells. This was also observed by Professor Kazutoshi Takahashi (Kyoto University, Kyoto, Japan), almost at the same time when Dr. Izsvák and Professor Hurst made their discovery.**

Dr. Izsvák and Professor Hurst succeeded in going one step further. They were able to identify the switch that regulates HERVH. In hESC cultures they identified a transcription factor – called LBP9 – as being central to the activity of HERVH in early embryos. Using a reporter system that made cells expressing HERVH via LBP9 glow green, the Berlin and Bath team found that they had purified human ESCs that showed all the hallmarks of naïve mouse stem cells.

This transcription factor was not previously known to be important to human stem cells. However, unknown to them at the time, the same transcription factor was shown by Austin Smith’s group (University of Cambridge, UK) to have a role in mouse naïve cells***.

“Our human naïve-like cells look remarkably like the mouse ones, and are close to human inner cell mass (ICM),” said Jichang Wang (PhD student, MDC), first author of the Nature publication. “With our HERVH-based reporter system we can easily isolate naïve-like human ESCs from any human ESC culture. These cells grow like the mouse naïve stem cells and express many of the same genes such as NANOG, KLF4 and OCT4 that are associated with murine naïveté. When we knockdown LBP9 or HERVH, these cells no longer resemble naïve-like human stem cells,” he added.

To explore a potential role in stem cell-based therapeutics, the next task will be to keep these isolated human naïve-like stem cells in culture and proliferate them. HERVH would also be particularly useful in identifying optimal conditions for long-term culturing. As HERVH inhibits differentiation, its expression should be transient, otherwise it might be detrimental to normal embryo development. What factors keep this delicate process in balance is yet to be determined.

What puzzled the authors, however, was the fact that HERVH is only seen in primates (monkeys, apes, etc.). “As an evolutionary biologist, this is the aspect I find most curious,” commented Professor Hurst. “One would expect that a mechanism as important as pluripotency would be conserved in different species of mammals,” he pointed out. “The mystery deepens,” added Dr. Izsvák. “We found one gene, called ESRG, whose sequence is almost entirely derived from the virus HERVH. We do not know which role ESRG plays. However, when we knock it down, the human naïve-like stem cells lose their pluripotency. ESRG appears to be specific to humans and does not occur even in our closest relatives, the apes”.

The HERVH-driven human-specific regulatory network could at least partially explain why mouse and human ESCs are basically different. Therefore Dr. Izsvák suggests comparing human naïve-like stem cells with the inner human cell mass rather than with mouse naïve cells.

“How then did we evolve circuitry particular to us?” asks Professor Hurst. “It is a real enigma – why does evolution tinker with something that doesn’t obviously need tinkering with? We know that some proteins related to LBP9 are important in suppressing viruses – perhaps this is at the heart of the conundrum?”

*Primate-specific endogenous retrovirus driven transcription defines naïve-like stem cells

Jichang Wang1&, Gangcai Xie1,2&, Manvendra Singh1, Avazeh T. Ghanbarian3, Tamás Raskó1, Attila Szvetnik1, Huiqiang Cai1, Daniel Besser1, Alessandro Prigione1, Nina V. Fuchs1,4, Gerald G. Schumann4, Wei Chen1, Matthew C. Lorincz5, Zoltán Ivics4, Laurence D. Hurst3*, Zsuzsanna Izsvák1*
1 Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
2 Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai 200031, China.
3 University of Bath, Department of Biology and Biochemistry, Bath, Somerset, UK, 
BA2 7AY.
4 Paul-Ehrlich-Institute, Division of Medical Biotechnology, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
5Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
& equal contribution
*Corresponding authors
http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature13804.pdf

**Ohnuki et. al. (2014) Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential, PNAS, 111, 12426-12431, August 26, 2014

***Martello et. al. (2013) Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor EMBO J. 32, 2561-2574)

Contact:
Barbara Bachtler
Press Officer
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
E-Mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/en

Katarina James
Research Marketing Manager
University of Bath
Phone: +44 (0)12 25-38 46 90
Cell phone: +44 (0) 74 03 66 97 18
E-Mail: K.James@bath.ac.uk
http://www.bath.ac.uk/

About the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
The MDC is one of 18 research institutions of the Helmholtz Association of German Research Centres. It is funded to 90 percent by the Federal Ministry of Education and Research (BMBF) and to 10 percent by the state in which it is headquartered, in this case Berlin. The MDC was founded in January 1992 to build the bridge between basic molecular research and clinical research. Under the umbrella of molecular medicine, MDC scientists focus on the research areas of cardiovascular and metabolic diseases, cancer as well as on diseases of the nervous system and on systems biology.

About the University of Bath
We are one of the UK's leading universities, ranked number one in the UK for student satisfaction for the last two years in the National Student Survey (NSS) and in the top ten of all national league tables, including being named ‘Best Campus University’ in the Sunday Times Good University Guide 2014. Our Mission is to deliver world class research and teaching, educating our students to become future leaders and innovators, and benefiting the wider population through our research, enterprise and influence. Our courses are innovative and interdisciplinary and we have an outstanding record of graduate employment. View a full list of the University's press releases or follow the University's latest news on Twitter.

Weitere Informationen:

http://www.pnas.org/content/111/34/12426
http://emboj.embopress.org/content/32/19/2561
http://www.dx.doi.org/10.1016/j.cell.2014.08.029

Barbara Bachtler | Max-Delbrück-Centrum

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>