Stem cell regulatory networks, dynamics and ways to engineer them (Day 1, TMM2016)

Author: Hamideh Emrani, 10/25/16

This year’s Till & McCulloch Meetings (TMM2016) began with a diverse set of topics organized into three different plenary sessions. The first session, on regulatory networks in stem cells, began with Sara-Jane Dunn from Microsoft Research who introduced us to “The Reasoning Engine for Interaction Networks, RE:IN,” a computational tool that can synthesize and analyze biological events happening inside cells. Such a program will help us better understand how cellular networks interact and ultimately be able to predict possible outcomes for interactions that have not been tested previously in lab settings.

Dr. Benoit Bruneau’s group, at the Gladstone Institute, is exploring how certain regulatory mechanisms at the DNA level can play a role in cardiac disease and congenital heart defects. Examples of such mechanisms are those involved in the binding of transcription factors and 3D formation of chromatin complexes. For today’s talk, the emphasis was on the transcriptional regulation of chromatin structures. The talk was fascinating, but since the data are not published yet, I am unable to go into specific details. (Sometimes you just have to be there in person!)

However, if this topic is of interest, you can learn about the effects of interactions of certain linear domains inside chromatin called Topologically Associated Domains (TADs), Transcriptional repressor CTCF, also known as 11-zinc finger protein, and cohesin and the effect they have on chromatin regulation and know that more will be revealed when the data from Dr. Bruneau’s lab get published. Consider this a teaser.

The afternoon started with a plenary session on stem cell dynamics seen among various stem cell populations, such as mammary stem cells during branching (Ben Simons of the Cambridge Stem Cell Institute) and malignant cell populations compared to normal ones (Connie Eaves, BC Cancer Agency).

One of the talks I especially liked was that of Derek van der Kooy, of the University of Toronto, who showed us two separate ways to change cell fate during differentiation of retinal stem cells. Retinal degeneration and the loss of photoreceptors is the primary cause of blindness in adults. Stem cells in the adult eye are located in the peripheral edge of the retina, but they have become quiescent through inhibitory factors released by the cornea during development. Therefore, alternate methods are being investigated to culture retinal progenitors in vitro and transplant them to the site of cellular loss.

Van der Kooy’s group has been able to grow retinal stem cells in global sphere formats in culture by adding different growth factors. And they discovered that there are two separate ways to change the fate of retinal stem cells into the two types of specific photoreceptors: rod and cone photoreceptors. You need to add Retinoic acid/Taurine (RA/T) or COCO to the differentiation media.

Taurine and Retinoic acid (RA/T) induce differentiation of rod photoreceptors (cells that stain positive for rhodopsin). If the RA/T are added in the last three days of retinal sphere growth and then are removed, the vast majority of the cells would differentiate into rhodopsin positive cells .Thus, RA/T acts in an instructive way on the early retinal progenitor cell to direct its fate towards a rod photoreceptor.

In comparison when there is a simple culture media such as FBS  only 1 per cent of the retinal stem cell population becomes cone photoreceptors. But if you add one small molecule called COCO (Coco Dand5 is a member of the Cerberus gene family) 60 to 70 per cent of the population become cone photoreceptors. COCO is a triple inhibitor of TGFβ, Wnt, and BMP. However, unlike the RA/T, which can only be added during the final three days of retinal sphere formation, COCO  has to be present the entire time of retinal cell culture. This shows that the differentiation into the cone photoreceptor only happens when the other differentiation pathways, that can lead to rod specific progenitors, are blocked.

It is fascinating how small manipulations to the culture media have such a high potential of being used in treatment strategies to overcome blindness caused by retinal degeneration.

The third session of the day was all about engineering stem cells and although it is not my area of expertise, I found two talks enlightening. I particularly enjoyed Aaron Wheeler’s talk where he presented digital microfluidics as a potential tool for stem cell culture, differentiation and analysis.

Digital microfluidics, is a technique where droplets of fluids are manipulated on a Teflon surface that has an array of electrodes underneath it. The device where the cells are seeded has two sides: the top plate and the bottom plate. Using electric fields one can manipulate the droplets and move them on the arrays. This has applications in studying and analyzing cellular pathways during cellular proliferation and differentiation.

Following his talk, Aspect Biosystems’ cofounder, Dr. Sam Wadsworth, introduced their innovative 3D bioprinting technique called “Lab-on-a-printer™” that enables scientists to design and develop tissues for drug testing applications and cellular culture in a really short amount of time.

And that is the sum of my take on the first day of TMM2016. It was really interesting to learn so much about the complex stem cell interactions and the innovative methods to analyze and replicate them in lab settings for treatment strategies. More coverage will come your way soon!

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Hamideh Emrani

Hamideh Emrani

Hamideh is a scientific communicator and the founder of Emrani Communications, serving clients in Toronto (University of Toronto) and California (Stanford University). She earned her B.Sc. in Cell and Molecular Biology at UC Berkeley and finished her M.Sc. at the University of Toronto (U of T). She was an intern at the Carnegie Institute at Stanford University, honours research student at UC Berkeley and has won awards for best podium and best poster presentations at the Faculty of Dentistry and IBBME at U of T. She is passionate about science and loves to talk and write about it. You can follow Hamideh on Twitter at @HamidehEmrani.
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