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The key to staying naïve

Key points:

• After noticing that many researchers keep human naïve embryonic stem cells in solutions containing TGFβ, researchers analysed genetic data and protein production to understand its effect on naïve embryonic stem cells.
• Dr. Rugg-Gunn’s team and his collaborators at the University of Cambridge found that TGFβ is needed for maintaining the stability of naïve embryonic stem cells.   
• Understanding the conditions needed to support the stability of embryonic stem cells is important for studying the earliest events in human development.

51����ers at the Babraham Institute and the (CSCI) have discovered the unexpected role of the signalling molecule TGFβ in maintaining human naïve embryonic stem cells. These stem cells are representative of the very earliest stages of human development and help scientists to understand the first molecular events that lead to every cell type of the body. The research, , is the first to establish a link between TGFβ signalling and naïve stem cell regulation, with the future potential to inform cell-based therapies and IVF treatment.

In 1998, scientists isolated human embryonic stem cells, providing huge potential for studying human development and cell decisions as they divide and specialise into any cell type in the body*. In the lab, embryonic stem cells are kept in conditions that maintain their unique powers of self-renewal and pluripotency, the ability to become any cell type. There are two types of embryonic stem cell, naïve and primed, which represent different stages of the embryo, behave differently, and specialise into different tissues. Both cell types are important to investigate in order to capture the full range of specialised cells.

The conditions that support primed cells are well understood, including the need to activate pathways that respond to the signalling molecule Transforming Growth Factor beta (TGFβ). However, the same isn’t true of naïve stem cells. Dr Peter Rugg-Gunn, group leader in the Epigenetics research programme, commented: “Until our study, researchers believed that naïve stem cells could be maintained in their pluripotent state simply by blocking differentiation signals. We noticed that TGFβ was a common component of many culture conditions that are used to maintain naive cells, and so we hypothesised that this signalling factor might have an unappreciated role in controlling naïve cell growth.”

After confirming their prediction that TGFβ signals were active in naïve embryonic stem cells, the researchers blocked the function of TGFβ to understand its role in maintaining the stem cells. Dr. Rugg-Gunn and his team observed that the growth of human naïve embryonic stem cells was disturbed and the cells spontaneously differentiated, even in conditions that normally supported their unspecialised state. These experiments revealed for the first time that naïve cells also rely on the TGFβ signalling factor for their growth. The researchers also discovered that protein messengers triggered by TGFβ help to activate other genes that maintain naïve embryonic stem cells in an unspecialised state.

Despite this similarity, the researchers found that the two cell types responded differently when TGFβ function was blocked. Where primed cells typically resemble early neuronal cells when TGFβ is blocked, the researchers discovered that naïve cells unexpectedly differentiate into cells that resemble trophoblast cells, which form part of the placenta. By subjecting cells to different conditions, and understanding the precise role of TGFβ in different cell types, researchers will be able to help to maintain human naïve embryonic stem cells in an unspecialised state.

Increasing the stability of naïve embryonic stem cells will allow for more robust research to be conducted in the future, Dr. Anna Osnato, lead author on the paper from Prof. Vallier’s group based at CSCI, explained: “Our findings could be used to develop better conditions to support the growth and ultimately the potential translational applications of naïve stem cells. For example, this could in the longer-term lead to improved cell-based therapies to treat conditions such as wound healing. More research is needed but our findings raise the possibility that TGFβ might also play an important role in supporting the unspecialised cells in the developing early human embryo.”

Investigating this exciting finding further could lead to its use as a biomarker of healthy embryo development and also to improve embryo culture conditions that are used in IVF, potentially leading to increased fertility success rates.

*Thomson et al. Embryonic Stem Cell Lines Derived from Human Blastocysts, Science

Notes to Editors

Publication reference

Osnato et al. , eLife

Press contact

Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk

Image description: Artistic depiction of embryonic stem cells

Affiliated authors (in author order):

Christel Krueger, Bioinformatician, Epigenetics research programme

Simon Andrews, Head of the Bioinformatics Group

Amanda Collier, former PhD student, Rugg-Gunn lab

Peter Rugg-Gunn, Group Leader in the Epigenetics research programme

51���� funding

This research was funded by the Biotechnology and Biological Sciences 51���� Council (BBSRC), the Medical 51���� Council, the Wellcome Trust; the European 51���� Council, and Cancer 51���� UK.

Additional/related resources:

Rugg-Gunn lab page

News, 18th November 2020: Single-cell technique could provide ‘egg health’ indicators

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 51���� Council (BBSRC), part of UK 51���� and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

About BBSRC

The Biotechnology and Biological Sciences 51���� Council (BBSRC) is part of UK 51���� and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.