Special stem cells

14 January 2018

Interview with

Peter Rugg-Gunn, Babraham Institute

This month on Naked Genetics we  journey back in time to the earliest moments in life as a foetus grows in the womb. Our story starts at the moment of fertilisation, when egg and sperm meet, creating a fertilised egg or zygote...

This single cell, somehow containing all the information needed to make a baby, divides to form an embryo, made up of special stem cells. In turn, these stem cells divide and specialise, eventually making all the tissues of the body. So how does that work?

In search of these hidden biological secrets Kat Arney went on a journey of her own - up the M11 to the Babraham Institute just outside Cambridge - to meet some of the UK’s leading developmental biologists.

Peter Rugg-Gunn, group leader at the Babraham Institute is fascinated by so-called pluripotent stem cells - cells that can turn into all kinds of different tissues. Kat wanted to know why exactly are they so interesting?

Peter – So pluripotency is a particularly remarkable state. Basically, what we can do is we can maintain stem cells in an unspecialised form in the Petri dish and they can undergo this process called self-renewal where they just can continually make new copies of themselves.

But then you can trigger the cells to specialise, to differentiate. You can coax them down different lineages and pluripotency is the ability to then specialise into all of the different cell types in our bodies.

That partly underlies a lot of the excitement and the promise of using stem cells in regenerative medicine - if you want to make a new pancreatic beta cell for instance then pluripotent cells offer a good starting cell material for that.

Kat - When people think about stem cells, they might think about like the stem cells in the very, very early embryo. The little clump of stem cells that become everything in the body and those are often described as totipotent – they can become everything. What's the difference between totipotency and pluripotency?

Peter - Absolutely. So totipotency is the ability of the cells to form any cell type possible so in particular, it includes all the extraembryonic cell types such as the placenta. Pluripotent cells have the ability to form the cells in the adult body. But it can't form cells like the placenta anymore.

I think you’ve touched on a good point there. What's remarkable is that in the human embryo for instance, there's about 10 or so of these pluripotent cells in this 7-day old embryo and these 10 cells make all of the different trillions of cells in our bodies, and I think that’s a very remarkable process.

Kat - It is. That’s why I wanted to become a development biologist. I'm like, “wow! How does that work?” So, how does that work? What is going on when a cell is pluripotent, when it can either make more of itself or go off down a pathway to become other types of cells? What's going on there?

Peter - So I think the important thing to remember here is in the embryo itself, the cells are pluripotent in that they can make all the different cell types, but they don’t remain in a pluripotent or unspecialised state for very long in the embryo. It’s actually quite a transient stage.

In the laboratory, when we grow the human pluripotent cells in a Petri dish, then we can really capture the cells for a long period of time – several years at least – in this undifferentiated state and then drive them to specialise. And so really, it offers a good system in which to ask questions along the lines of what you’ve just asked me.

You know, the simple answer is we don’t know, but we get a lot of cues from different species in development so we can get a good understanding of what signals might be involved from reading about the fruit fly or the mouse, etc. And often, these mechanisms are conserved. And so, we can apply these different chemicals to the human stem cells in a dish and often, they can trigger the same form of cell differentiation.

I think what's exciting in the field right now is we’re also understanding more about how the human embryo develops. There's a lot of discussion and dialogue at the minute about this. Just recently for example, a paper was published where they began to look at the gene expression road map of human pancreatic cells as they develop in the human embryo.

And now, we have this benchmark in which to compare our stem cell differentiation too, so we know whether the stem cells are going down the right line towards becoming a pancreatic cell and how similar is that to how a human embryo does it.

Kat - We’ve talked a lot about embryonic cells and one of the big buzz words at the moment is IPSCs or Induced Pluripotent Stem Cells. So, how do they relate to the kind of pluripotent cells that you find in an embryo? Where do they come from?

Peter - Right. So IPS cells are reprogramed cells, basically. So, this discovery was awarded the Nobel Prize just a few years ago and what the discovery was that you can take any cell type, typically a skin cell, and you can add fairly small set of genes, genetic material which we know is involved in pluripotency.

And over a period of a few weeks, those skin cells slowly transform and reprogram into a cell type that’s very, very similar to a pluripotent cell that you might get from an embryo for example. And they seem to have similar properties. You can grow them in similar ways and then they can re-specialise into any other cell type.

Kat - So now we can take pluripotent stem cells that you’ve got in the lab and you can treat them with certain factors and they will become all sorts of different types of tissues. You can then take cells that have differentiated into a tissue and wind the clock back. This is a very powerful position to be in. So, what can we do with this knowledge? What do we do now that we can wind cells forward and wind them back?

Peter - That’s a great question. One of the things I'm most excited about is, what are the epigenetic and the genetic regulators of this reprograming and then also the forward programing? So, for example, now we can use some of these new genetic tools like CRISPR that’s available to us.

We can then use these technologies to then delete genes at will and then we can ask whether those cells can now reprogram back to a pluripotent state or not. If they can't, that tells us those genes are necessary for reprogramming and then it gives us a clue as to look into those genes and ask why might they be necessary.

So this system is really very powerful way now to try and understand what are regulators of these processes – how do cells get from A to B, basically – and now, we can begin to understand what those regulators might be.

Kat - There's a lot of excitement about using stem cells, using IPS cells for tissue engineering. Okay, you want to build pancreas, let’s take some cells, wind them back, turn them into pancreas cells. Where are the limits? What do we still need to be able to do? I mean, can we basically make all the bits of a human yet? Basically, when am I going to get replacement body parts?

Peter - Yeah. Well a few years ago, that might have been science fiction but now, it’s becoming a bit closer. So there are already clinical trials now out there for diabetes and soon there’ll be for the Parkinson's disease and some of this other degenerative diseases.

Some of the problems we still have, some of the data out there suggested that the cells we’re producing are not truly adult in nature but maybe more foetal-like. And so, that might be okay in some situations but on the other hand, foetal cells are known to express different enzymes and different levels of proteins and things like this.

So whether they can really be truly functional in a disease situation, I think is still not known. Also, we still don’t really know about some of the safety aspects of some of these therapies right now and that again is a big area that people are working hard towards.

Kat - So, you’ve got your pluripotent cells in a dish and you're like, “okay, we want to make heart muscle.” What's the first step? Can you just go straight from stem cell to heart muscle? Do you have to kind of take them through a ‘training program’ basically?

Peter - There's different ways to do it. I think the most effective way, the way most people do it is to try and recapitulate their elements to take them through these sort of building blocks that the embryo uses in order to make heart, for example.

So in terms of that, you would first make mesoderm so you might have a sprinkling of BMP and Wnt in there and then once you made that cell type, you go on to make the next cell type, and so on. And you can really think about it in different stages.

But there are some remarkable studies out there where people seem to have gone directly from one cell type to another cell type, often by overexpressing genes which we know are important in a particular cell type and what intermediate stages they go through? I think who knows, really?

Kat - That sounds like an incredible hack, isn’t it? Like, do not pass, go, just go straight to brain cell.

Peter - Yeah, exactly that. What other cell types can we go straight towards and how does it work?

Kat - When you're thinking about things from an epigenetic point of view, we know that as we go through life, we still keep the same genes but stuff changes. Epigenetic marks get put on, get taken off. Does it matter what age you are when you try and make stem cells? How did those marks get retained or lost as people are moving cells through these different stages?

Peter - Absolutely. So, the data that I'm aware of, if you reprogram a skin cell, for example, from an elderly donor back into one of these pluripotent IPS cells, it seems as though most of the hallmarks of ageing is removed, is reversed essentially, and the cells become young, if you will, again so their methylation or epigenetic clock is set back to zero again.

And then as cells then get re-specialised, it seems like the clock starts again, but in a fairly normal way. So, the resultant specialised cell that you get at the end doesn’t seem to be prematurely aged to any different to what you would expect.

Interestingly, if you make a specialised cell directly from say, an elderly skin cell then in that direct route, it seems to retain these hallmarks of the aged cell to begin with. So it seems like if you go through this pluripotent phase then somehow, some of these hallmarks get removed.

Kat - That’s very interesting. As I get older, I'm like, “Ooh! How can I make myself younger?” So you're saying, I’ll basically have to reprogram all my cells to a pluripotent state and start again.

Peter - Yeah. I'm not sure I’d recommend it quite yet for therapy.

Kat - Peter Rugg-Gunn, and his pluripotent stem cells.

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