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Stem cells

Ever wondered where your blood comes from?

We all find out at a pretty young age what our blood is: often due to unfortunate incidents as toddlers involving overambitious attempts to run/jump/climb over household objects twice our height. But despite almost continually losing blood throughout our lives via cuts, grazes, injections and other incidents we almost never run out of the stuff, except in extreme circumstances. This is because your body is constantly producing blood to make up for that which is lost during daily life – but where does this new blood come from? This is a tricky question to answer, but a study led by Rui Monteiro in Roger Patient’s lab in the MRC Molecular Haematology Unit sheds new light on this complex process. Tomasz Dobrzycki, a DPhil student in the lab, explains what they found.

Each of us has around 6 pints of blood. The blood contains a number of different types of cell, including oxygen-transporting red blood cells, disease-protecting white blood cells or wound-closing platelets.

But do you know where they all come from?

Quite amazingly, all these very different blood cells originate from the same parental cell, called the haematopoietic stem cell (HSC for short). A number of HSCs live inside our bone marrow and keep making new blood cells throughout life.

That’s why you don’t have to worry if you cut yourself and lose some blood – your bone marrow will make new cells very quickly. In fact, a single haematopoietic stem cell has the potential to make all 6 pints of your blood itself!

At the MRC WIMM we are trying to understand where the HSCs themselves come from in the first place. In other words, our aim is to precisely describe the very first origins of the blood in the human body.

We actually need to look quite early, because the whole process starts long before we are born – around 6 weeks into pregnancy. Luckily, we do not need human embryos to do our research: the process of making the very first HSCs is very similar across all vertebrates, so a lot of discoveries in the field with relevance to human biology have been made using mouse, frog or zebrafish embryos.

In Roger Patient’s lab in the MRC Molecular Haematology Unit we work with zebrafish and frogs to identify the molecules responsible for making the first HSCs.

But understanding these chemical signals is a complex process. Making a haematopoietic stem cell is like cooking a complicated dish: you cannot just throw all the ingredients into a pot, put it in the oven and hope that a perfect meal will come out. You need to add things in the correct order, mixing and cooking by following precise guidelines. If you throw raw beef on top of pre-boiled pasta sheets, tomato sauce and cheese, trust me – you won’t be eating lasagne for dinner.

lasagne

Producing blood requires the careful addition of the right ingredients in the right order, just like cooking certain complicated dishes. Image credit: Pierre Wolfer via Flickr.

In the case of the developing embryo, the ‘ingredients’ are molecular signals and genes. In order to make an HSC, the embryo needs to deliver the appropriate signals and turn on the expression of essential genes at the right time and in the correct order. In a recent paper by Rui Monteiro and colleagues, published in Developmental Cell, the team describe not only the precise timing when these specific signals need to be delivered to the future HSCs during the development of the embryo, but also which signals need to arrive first.

Through a series of careful experiments using zebrafish embryos, the team worked out that a pathway of signals involving a key molecule called TGFβ which is known to regulate stem cells in other contexts also plays a key role in developing HSCs. What is important, they managed to place this signal within the broader network of other pathways involved in programming the blood stem cells.

But the paper goes beyond that, mainly because of one complication with TGFβ. There are a number of different molecules in the TGFβ family (TGFβ1, TGFβ2, TGFβ3), all of which trigger very similar events in their target cells – but are all subtly different.

Sticking to our cooking analogy – imagine if the recipe instructed you to add pepper. If you add jalapeño pepper instead of yellow pepper – although these two are both called ‘pepper’ and are related – you may ruin your dish by adding the wrong one.

Rui Monteiro and his team managed to identify a similar scenario with the TGFβ signals required for making the first HSCs. Although the team found that both TGFβ1 and TGFβ3 are required to make the HSCs, both of them come from different sources and are required at different times during the development of the embryo. This finding really puts emphasis on how important it is to remember the correct timing of events when studying embryonic development at the molecular level. It really is a lot like cooking, isn’t it?

How can understanding the origins of our blood be useful in the long term? If we discover enough pieces of the puzzle, we may be able to write down a trusted ‘recipe’ to make haematopoietic stem cells in a laboratory dish, step by step. Such optimised, lab-grown HSCs would have a great potential to help people suffering from various blood disorders, including leukaemia, who require regular transfusions of particular types of blood that are often hard to come by. Let’s hope we’ll be able to start ‘cooking’ soon!

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