Multiple filters for stem cell research at Canadian stem cell conference

By Samantha Yammine, PhD Candidate in Derek van der Kooy’s lab at the University of Toronto. See tweets live from #TMM2016 via @SamanthaZY here.

Whistler, BC, Canada.

The location of this year’s annual TMM in Whistler, BC, Canada.

Last week, 430 Canadian scientists, trainees, industry professionals, science communicators and international guests gathered in the picturesque ski town of Whistler, British Columbia for the annual Till & McCulloch meeting (TMM). This is Canada’s premier conference for stem cell research, which is co-hosted by the Centre for Commercialization of Regenerative Medicine, the Stem Cell Network, and the Ontario Institute for Regenerative Medicine.

Continue reading

Fuzzy New Stem Cells Bring Reprogramming into Focus

F-class stem cellsHow cool is it that literally fuzzy new stem cells called “F-class cells” bring substantial new sharp focus to the cellular reprograming arena?

Remember Project Grandiose led by the great stem cell scientist Andras Nagy?

It’s a massive project intended to decipher what makes stem cells tick and how ordinary cells be changed or reprogrammed into powerful pluripotent stem cells that can make any other type of cell.

I’ve heard Nagy speak before about it at meetings and this blog first reported on these fuzzy cells last year here (Jailbreaking Cell Fate Reprograms to Multiple Stem Cell Types, Says Nagy, Not Just iPS cells).

This “think big” Grandiose team has come out today with five new papers in Nature and Nature Communications on the fuzzy new type of stem cell fitting into the most powerful pluripotent class of stem cells.

The team calls these new cells “F-class’ because the colonies that they make in a dish are fuzzy compared to the compact colony type more commonly seen in pluripotent cultures of ES cells or induced pluripotent stem cells (IPSC). See image above from one of the papers from the Grandiose team.

F-class pluripotent cells are an interesting new type of pluripotent stem cell. While these cells appear to be relatives of IPSC and of ES cells, they have some potentially important differences as well such as requiring sustained reprogramming factor expression to maintain their identity.  F-class cells also have some differences in gene expression and in their epigenomes compared to other types of pluripotent cells. For example, specific histone lysine methylation (H3K27me3) and DNA methylation are implicated.

The quintet of papers from Project Grandiose together report an amazingly large amount of data (you can see the actual data here) on both F-class cells and reprogramming more generally fitting with the “Grandiose” name. This data is like a Buffalo snowstorm so it will take some time for the field to “dig out” and dig into the drifts of data to entirely digest the meaning of it all, but it seems to be a major step forward in understanding controllable pluripotent states.

Some exciting questions remain for future studies.

Can human F-class cells be produced?

The team shows that F-class cells have some differentiation potential, but I’d like to learn a lot more about how these cells differentiate into specific types of functional cells compared to those produced from ES cells and IPSC.

Are F-class cells more tumor-like than IPSC and ES cells given that the F-class cells require continued reprogramming factor expression? If so, would F-class cells pose a higher risk from a clinical perspective?

I’m most excited about the concept that there can potentially be many different kinds of reprogrammed states and pluripotent states. With the arrival of F-class cells on the scene along with IPSC and ES cells, whose to say that there aren’t additional types of pluripotent cells with unique properties that might be harnessed clinically such as G-class, H-class, and so forth?

It seems that as time goes by since the discovery of IPSCs and flexible cell types we scientists need to be more flexible in our thinking as well.

Jailbreaking Cell Fate Reprograms to Multiple Stem Cell Types, Says Nagy, Not Just iPS cells

Andras NagyYou can jailbreak your iPhone, but perhaps you can jailbreak a cell too to turn it into a stem cell.

In his very cool talk up here at the Till & McCulloch Meeting on Stem Cells yesterday, Andras Nagy characterized the reprogramming process to make iPS cells as “jailbreaking” cell fate. Nagy described some intriguing studies done on reprogramming by his lab together in collaboration with an international consortium.

I especially appreciated the fact that Nagy (see pic at left, credit to Peter Raaymakers) tackled head on an “elephant in the room” issue in the iPS cell field: cellular reprogramming produces a heterogeneous mix of stem cell types. This unfortunate reality has been quietly reported on in papers and discussed at stem cell meetings for years. Many of colonies produced by the most common iPS cell reprogramming methods are not iPS cells and this phenomenon has meaning.

What are these other colonies?

Some are pre-iPS cells, which didn’t quite make it to full pluripotency. Others are likely iPS cells that made it to full pluripotency, but were unstable and differentiated. Still other byproducts of the iPS cell process are colonies of cancer cells. I noted the similarity of iPS cell methodology to “old-fashioned” oncogenic foci assays used to study tumorigenesis in a review 4 years ago and then in a somewhat controversial research paperInduced Pluripotency and Oncogenic Transformation Are Related Processes, about 10 months ago.

Nagy focused in his talk on two main types of stem cells produced by the reprogramming process: true iPS cells and so-called “F cells”.

The F class stem cells made by reprogramming are in fact nearly pluripotent, Nagy reported. They are able to form “beautiful” teratoma, but they don’t form chimeric mice so in fact they are not quite as fully pluripotent.

When Nagy’s team looked at gene expression changes in the F cells compared to starting fibroblasts, the alterations tended to more extreme in F cells as opposed to iPS cells. It’s almost as if in the F cells the reprogramming factors did their jobs but went too far to yield too much of a good thing leading to a suboptimal result.

They asked if they could find small  molecules that would make the F cells behave more like iPS cells and found that histone deacetylase (HDAC) inhibitors did the trick, now making the F cells able to form chimeric embryos. Thus, Nagy asserted that genomic acetylation is an obstacle to reprogramming.

In an effort that he himself has dubbed “Project Grandiose”, Nagy’s team is throwing everything but the kitchen sink in the way of Omics assays at iPS cells and F cells in a dynamic time course of reprogramming.

The results so far are intriguing with one conclusion being that most of the elements of reprogramming happen surprisingly fast, except for DNA methylation changes. This is interesting at least in part because they do see transcription changes happen fast, well before changes in DNA methylation even though DNA methylation is of course thought to change gene expression. So it seems that there is more to DNA methylation’s role in reprogramming than impacting transcription.

I can’t wait to see more on the Nagy teams efforts in this area.