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 Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>