ISSCR Day 1: Escaping the ground state of pluripotency

Author: David Kent, 06/24/16

The 2016 Annual Meeting of the International Society for Stem Cell Research got off to a fantastic start Wednesday night in San Francisco. Two excellent sessions were delivered to a packed house with talks ranging from the importance of circular RNAs (Pier Paolo Pandolfi) through to a pretty incredible description of the cellular biomechanics of development in the fruit fly (Jennifer Zallen). The talk that stood out most for me, however, was the one that received the McEwen Award for Innovation.

Awarded by Canadian philanthropists Cheryl and Rob McEwen, the award is meant to highlight breakthrough discoveries that advance stem cell biology. It was an absolute delight to see this year’s award going to a pair of researchers who are heavily invested in understanding the very fundamental biology of embryonic stem (ES) cells. All too often, recognition is doled out to the final piece of the puzzle from a translation perspective (e.g., treatment that cures disease), but this award recognizes the basic discoveries in the most primitive of stem cells made by Austin Smith and Qi-Long Ying.

Professor Smith described the published portion of the work with great precision and emphasized the contributions of other world leaders in defining the molecular regulators of mouse embryonic stem cells. The key feature of this work was improved handling of ES cells outside the body where it was discovered that by inhibiting the activators of fate choice commitment, one could keep ES cells in a relatively homogeneous, primitive (or “naïve”) ground state.

By reducing the number of contaminating cells in these cell cultures, you improve the purity of the ES cell cultures. This increased purity sets the stage for understanding which molecules drive the decision to become a non stem cell. What keeps a stem cell as a stem cell and what factors drive it away from this ground state are fundamental questions in stem cell biology.

And this is exactly what Professor Smith went on to describe. Following on from their substantial efforts to develop tools that reliably mark stem cells and functional screens that identify regulators of the transition, the Smith group made a surprising discovery: cells do not actively commit to a particular cell fate immediately, but rather they first require “release” from the ground state before commitment. Professor Smith described this interesting stage as a “dynamic metastable state of heterogeneous primed ES cells” and showed that it exists both in cell culture dishes as well as in the embryo during development.

So, in short, it appears that stem cells can only exist by avoiding inductive stimuli in an effort to preserve their robust self-renewing state. Once released from the ground state, cells must first transition into a “primed” state where their future cell fate choices can subsequently be determined by cell type specific factors that specify which type of cell gets produced. This tri-phasic transition from pluripotent cells to committed cells was further supported with a suite of transcriptional and epigenetic studies that described the molecular changes driving the process.

Overall, Professor Smith’s presentation was a fascinating glimpse into the early stages of the mouse embryo and the cell fate choices required to progress to mature cell types. These fundamental observations about the stem cell ground state, and how individual cells must make the journey through a primed state toward specification, are essential to understanding mammalian development and (eventually!) for mimicking this process outside the body in an effort to provide cell therapies and develop drug-screening platforms.

Only through these discoveries in basic biology, achieved through a rigorous approach to scientific questions like those asked by Drs. Smith and Ying, can we hope to progress in the field. I applaud the McEwen’s for rewarding such efforts and encouraging these forays into the nuts and bolts of how stem cells work.

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David Kent

David Kent

Principal Investigator at University of Cambridge
Dr. David Kent is a Principal Investigator at the University of Cambridge in the Cambridge Stem Cell Institute ( His laboratory's research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole in 2009. He has been writing for Signals since 2010.
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