Why stem cells need to stick with their friends

Scientists at the University of Edinburgh and University of Copenhagen have identified a core set of functionally relevant factors which regulates embryonic stem cells’ ability for self-renewal. A key aspect is the protein Oct4 and how it makes stem cells stick together. The identification of these factors will be an important tool in devising better and safer ways of making specialised cells for future regenerative cell therapies for treatment of diseases like diabetes and Parkinson’s disease.

Scientists have known that the protein Oct4 plays a key role in maintaining the embryonic stem cells in pure form by turning on stem cell genes, however up until now it has not been know which of the 8000 or more possible genes that Oct4 can choose from actually support self-renewal.

By comparing the evolution of stem cells in frogs, mice and humans, scientists at the MRC Centre for Regenerative Medicine and the Danish Stem Cell Center http://danstem.ku.dk/ in Copenhagen have now been able to link the protein Oct4 with the ability of cells to stick together. They found that for embryonic stem cells to thrive they need to stick together and Oct4’s role is to make sure they stay that way.

“Embryonic stem cells can stay forever young unless they become grown-up cells with a specialised job in a process called differentiation. Our study shows that Oct4 prevents this process by pushing stem cells to stick to each other.” said Dr Alessandra Livigni, Research Fellow at the University of Edinburgh's MRC Centre for Regenerative Medicine.

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'Image shows how embryonic stem (ES) cells stick together (green, left image) when they express Oct4 protein in the cell nuclei (magenta, left). When Oct4 is removed their shape changes and their adhesion to each other is reduced (right panel, nuclei in blue). Image by Dr Alessandra Livigni, MRC Centre for Regenerative Medicine.'

Identification of specific genes The research teams in Edinburgh and Copenhagen successfully identified 53 genes, out of more than 8000 possible candidates that together with Oct4, functionally regulate cell adhesion. Almost like finding needles in a haystack the scientists have paved the way for a more efficient way of maintaining stem cells as stem cells.

"Embryonic stem cells are characterized, among other things, by their ability to perpetuate themselves indefinitely and differentiate into all the cell types in the body – a trait called pluripotency. Though to be able to use them medically, we need to be able to maintain them as stem cells, until they're needed. When we want to turn a stem cell into a specific cell for example; an insulin producing beta cell, or a nerve cell like those in the brain, we'd like this process to occur accurately and efficiently. We cannot do this if we don't understand how to maintain stem cells as stem cells,” said Prof Joshua Brickman from the Danish Stem Cell Center, University of Copenhagen.

Future potential As well as maintaining embryonic stem cells in their pure state more effectively, this new insight will also enable scientists to more efficiently manipulate adult cells to revert to a stem cell like stage known as induced pluripotent stem cells (iPS cells). These cells have many of the same traits and characteristics as embryonic stem cells but can be derived from the patients to both help study degenerative disease and eventually treat them.

“This research knowledge has the potential for us to change the way we grow stem cells, enabling us to use them in a less costly and more efficient way. It will help us devise better and safer ways to create specialised cells for future regenerative medicine therapies,” concludes Prof Joshua Brickman. The findings were published in scientific journal Current Biology on 7 November 2013.

Notes to editors

About MRC Centre for Regenerative Medicine (CRM) The MRC Centre for Regenerative Medicine (CRM) is a world leading research centre based at the University of Edinburgh. Scientists and clinicians work together to study stem cells, disease and tissue repair to advance human health. Research at CRM is aimed at developing new treatments for major diseases including heart disease, degenerative diseases such as multiple sclerosis and Parkinson's disease, and liver failure. www.crm.ed.ac.uk.

About DanStem The Danish Stem Cell Center (DanStem) opened in the summer of 2011 and is the focal point for international basic, translational and early clinical stem cell research. Professor Joshua Brickman and his team came to DanStem from University of Edinburgh, Scotland in October 2011. Together with three other internationally recognised research groups – recruited from Switzerland, Sweden and Denmark – they constitute the core of the center. DanStem addresses basic questions about stem cells and developmental biology in order to develop new stem-cell based treatment methods for diabetes and cancer. The Danish Stem Cell Center is supported by two large grants from the Novo Nordisk Foundation (DKK 350 million) and The Strategic Research Council (DKK 64.8 million), respectively. http://danstem.ku.dk

About Stem Cells and Embryonic Stem Cells Stem cells are distinguished from other cell types: they are unspecialized cells capable of renewing themselves through cell division, and under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, such as the pancreas and the heart, stem cells only divide under special conditions.

Embryonic stem cells are grown from cells found in the embryo when it is just a few days old. In humans, mice and other mammals, the embryo at this stage is a ball of approximately 100 cells forming an outer layer and an inner clump. The cells in the inner clump are pluripotent: they can make every type of cell in the body. They will multiply and differentiate (develop into more specialized cells) extensively to make the many types of cells needed to form the entire animal. Read more at EuroStemCell.org.

Livigni A, Peradziryi H, Sharov AA, Chia G, Hammachi F, Portero Migueles R, Sukparangsi W, Pernagallo S, Bradley M, Nichols J, Ko MSH, Brickman JM. 2013. A Conserved Oct4/POUV-Dependent Network Links Adhesion and Migration to Progenitor Maintenance. Current Biology, 7 November 2013. Epub ahead of print. doi:10.1016/j.cub.2013.09.048.