Austin Smith talk at ISSCR 2016: a ground state inhibitor pathway

ISSCR 2016’s first plenary session is focused on stem cells & cancer. I was really excited about this one even before the meeting as this topic is a major focus of my own lab.

Here’s the lineup for this plenary with great expertise in stem cells & cancer from across the globe:

• President’s Address: Sean Morrison, Children’s Research Institute at UT Southwestern, USA
• 2016 McEwen Award for Innovation Presentation: jointly, Austin Smith, Wellcome Trust Centre for Stem Cell Research and Institute for Stem Cell Biology, UK and Qi-Long Ying, University of Southern California, USA
• 2016 McEwen Award Lecture:  Austin Smith, Wellcome Trust Centre for Stem Cell Research and Institute for Stem Cell Biology, UK 
• John Dick, University Health Network, Canada
• Irving L. Weissman,  Stanford University, USA
• Elaine Fuchs, Rockefeller University, USA
• Pier Paolo Pandolfi, Beth Israel Deaconess Medical Center, USA

In blogging this, the post will be more of a stream of consciousness and notes so keep that in mind as you read. This particular post will primarily focus on Austin Smith’s talk.

Before Dr. Smith spoke, ISSCR President Sean Morrison told us that this is the largest ISSCR meeting by far in terms of attendees. He also highlighted ISSCR policy programs including the importance of unimpeded research including fetal research, which has had a major, positive impact. Next came some words from the Chair of CIRM, Jonathan Thomas (JT) about the focus of CIRM moving forward. He talked about the bold, exciting goal of funding 50 clinical trials.

The McEwen Award was given to Smith and Qi-Long Ying. Congrats to them!

Dr. Smith gave the award lecture with the title “Escape the ground state.” 2i/LIF mESCs are true ES cells and the same is true for rat ES cells made in this way. He focused on the ground state network. When the network activity winds down the ES cells move toward commitment and the MAP kinase pathway is activated. They screened for more commitment factors using a Rex1-GFP reporter. This screen ID’d other factors that inhibit the ground state network including NuRD.

What’s ERK doing here? They found this interesting factor called Etv5 downstream of ERK. Etv5 is within the PEA3 subfamily of Ets factors. Etv5 and Etv4 are induced during differentiation of ES cells (16-25 hours). Etv5 is also relatively highly expressed in the ES cells, while Etv4 is much higher after differentiation. Etv4/5 double knockdown impairs transition to differentiation. The Etv4/5 knockdown leads to continued colony formation even within the differentiation context. They also did knockout work finding the same outcomes. Like Etv4/5, Etv5 and Tcf3 knockouts don’t differentiate properly. An overall conclusion of this part of the talk–Etv4/5 are central targets of FGF/ERK pathway that mediate progression away from naive pluripotency.

What happens to ES cells that lack Etv4/5 and LIF? They change dramatically in morphology. He next talked about comparing REX1-GFP lo and high cells. Lo cells are pluripotent and can respond to germline induction. They looked at DNA methylation in the lo cells and they had an intermediate level. In the lo cells, naive ES cell specific enhancers have increased methylation intermediate between ES cells and E6.5 embryos.

The key big picture hypothesis is that there are 3 parsable phases of pluripotency: naive, formative, and primed.

He closed with key open questions.

How do cells navigate between these phases? What are the molecular events that confer competence? How similar is the unfolding of pluripotency in human versus these mouse studies that were the focus of the talk?

Great stuff!