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Stem cells

Specifying stem cells, specifically

Your blood is made up of many, many different types of highly specialized cells: white blood cells to fight infections; red blood cells to carry oxygen; and platelets to allow your blood to clot (to name but a few). Scientists now know that all of these diverse cell types originate from a single parent cell – the blood (or haematopoietic) stem cell, which is found in the bone marrow. These rare stem cells have huge clinical potential for helping to cure people with devastating blood-related diseases such as leukaemia, but to date little has been known about where these cells themselves originate. However, new research from Roger Patient’s lab helps to shed light on how these unique cells are made. Bryony Graham explains more.

Bone marrow transplants save lives. It’s as simple as that.

The reason bone marrow transplants are so effective is because the bone marrow is home to an incredibly rare, powerful type of cell called a blood or haematopoietic stem cell. For your entire life, these cells sit in the squishy tissue in the middle of your bones happily producing every single blood cell that will ever circulate around your body.

Scanning electron microscopy image of haematopoietic stem cells budding from the aortic endothelium. Image credit: http://www.hubrecht.eu/research/robin/research.html

Scanning electron microscopy image of haematopoietic stem cells budding from the aortic endothelium. Image credit: http://www.hubrecht.eu/research/robin/research.html

This remarkable property of haematopoietic stem cells means that if anything goes wrong with your blood, it is possible to remove your own bone marrow (which, for whatever reason, is producing sub-optimal cells) and replace it with somebody else’s bone marrow which is doing the job just fine.

Sound too good to be true? Well, in some cases – it is. In order for a bone marrow transplant to be successful, the donor and recipient have to have similar immune systems, otherwise the recipient recognizes the new cells in the bone marrow as an invading foreign object (like a bacterium or virus) and mounts an immune response against them. And even if the new cells are accepted by the recipient, sometimes there are just too few of them to be effective.

So, an alternative way of replacing the haematopoietic stem cells in patients with blood disorders is required, and has been the target of many research teams around the globe for years. The golden goal is to be able to generate haematopoietic stem cells in the lab that are genetically matched to the patient, and therefore should be accepted when put back into the bone marrow – but as you can imagine, this process isn’t trivial.

One major stumbling block in achieving this goal to date has been a fundamental lack of understanding of how, where and when these cells actually originate in the first place; how can we possibly attempt to mimic this process in the lab if we don’t know how it works in in a living, breathing organism?

This is exactly the question that scientists in Roger Patient’s lab at the WIMM have been asking, and have published their latest findings in Nature Communications.

It is known that during embryonic development, haematopoietic stem cells originate from a layer of cells on the developing major artery (or aorta). This process is believed to be extremely transient, and is regulated by a complex array of signals that originate in various parts of the developing embryo, telling the haematopoietic stem cells exactly when and where to form.

Despite this knowledge, attempts to recapitulate haematopoietic stem cell formation in the lab using these signals have been unsuccessful. However, scientists in the Patient lab have found another family of proteins involved in this process in zebrafish, which they hope could help to develop more efficient strategies to generate patient-specific haematopoietic stem cells.

These proteins are collectively involved in a cascade of signals called the FGF signaling pathway, which has been known to play a role in many other developmental processes for some time, but has never been implicated in haematopoietic stem cell formation before.

Now, the Patient lab have shown that for a very brief window of time, this signaling pathway actually has a repressive role in haematopoietic stem cell formation, and they speculate that this might be a key step which is missing from attempts to recapitulate this process in the lab.

Generating a consistent supply of haematopoietic stem cells in the lab holds huge promise to provide hope to the many people for whom bone marrow transplants fail. Understanding this incredibly complex process is hugely challenging, but this new study from the Patient lab at the WIMM takes a significant step in the right direction to making this novel therapeutic strategy a reality.

Post edited by Roger Patient.

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