Wiping the slate clean: erasing cellular memory and resetting human stem cells

Wiping the slate clean: erasing cellular memory and resetting human stem cells

Babraham Institute scientists, in collaboration with colleagues at the Cambridge Stem Cell Institute and the European Bioinformatics Institute, have published findings today in the journal Cell giving hope that researchers will be able to generate base-state, naïve human stem cells for future medical applications. The study demonstrates that human stem cells can be reverted back to a base state, losing characteristics that mark them as belonging to a specific cell lineage and instead regaining the identify of non-specialised cells with unrestricted potential (pluripotency) to develop into any cell type.

The study’s lead researchers, based at the Wellcome Trust-Medical Research Council Stem Cell Institute in Cambridge, reset human stem cells back to a pluripotent state. Previous work in mice had described the characteristics of base-state mouse stem cells and the group were able to show that these characteristics were largely shared by reset human pluripotent stem cells, giving confirmation that these human cells were indeed reverted to a naïve state.

Part of this analysis involved looking at the epigenetic regulation in the base-state human stem cells. This analysis was performed by Dr Gabriella Ficz, Professor Wolf Reik and their colleagues at the BBSRC-supported Babraham Institute, Cambridge. Epigenetics refers to the range of DNA modifications that affect gene expression but are not sequence-based. For example, chemical methyl tags on DNA can silence gene expression. Cells gain epigenetic markers as they assume a defined cell identify. Therefore, early embryo cells show a low level of methylation, corresponding to their lack of commitment to a particular cell fate. Last year, the Babraham group discovered a large-scale loss of methylation from the genome of reset mouse embryonic stem cells.

Ficz and Reik were able to show that, overall, the reset human stem cells showed a loss of methylation marks throughout the genome; they essentially had their epigenetic memories wiped clean. This low level of DNA methylation demonstrated their similarity to early embryonic cells and thus was a strong indication of their regained pluripotency.

Dr Gabriella Ficz, who undertook the epigenetic analysis of the cells as a post-doctoral researcher in Professor Reik’s group, said: “This study brings us one step closer to the ultimate aim in regenerative medicine of using patient-derived cells to avoid immune rejection in cell and organ replacement therapies. It’s all about finding out what the cell needs in order to survive and multiply while making sure that they have lost the memory of the tissue they came from. Both conditions need to be fulfilled for successful use of embryonic stem cells in tissue generation.”

Professor Wolf Reik, Group Leader at the Babraham Institute continued: “We can liken this reprogramming to giving cells amnesia so they forget any previous developmental decisions they have made. Returning them to this state means that we can then control their cellular decisions, allowing us to generate the particular types of cells needed. This area has huge medical potential, for example, being able to provide reset stem cells back to a patient that we can be confident will develop into the correct cell type as required, for example, nerve cells.”

Professor Michael Wakelam, Director of the Babraham Institute added: “This research is an enormous step forward in answering questions about whether human stem cells can be reset to a ground state and the feasibility of maintaining pluripotency. It is also an excellent demonstration of the importance of collaborative research making the most of the extensive and complementary expertise that can be found in Cambridge.”

The Babraham Institute’s research contribution to this study was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust.

Publication reference: Takashima et al. (2014). Resetting transcription factor control circuitry towards ground state pluripotency in human. Cell.

Louisa Wood, Communications Manager
The Babraham Institute
Babraham Research Campus
Cambridge CB22 3AT
United Kingdom
Notes to Editors:
About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
Website: www.babraham.ac.uk
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
Website: bbsrc.ukri.org/