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Stem cells, The immune system

From stem cell to specialized cell: but what happens in between?

Stem cells have the remarkable ability to develop into a whole host of highly specialized cell types, but the process by which this happens is extremely transient and therefore enormously challenging to study. However, a new paper from Claus Nerlov’s and Sten Eirik Jacobsen’s labs, published in Nature Cell Biology two weeks ago, is one of the first studies to show that the physical environment within which these elusive cells mature is critical to their development. Bryony Graham explains more.

So, stem cells are pretty clever.

There are two main types: embryonic stem cells (from which an entire human being is formed) and adult stem cells (which maintain all the bits of your body that need replacing – like your hair, your skin and your blood).

Stem cells are remarkable because they can develop into many, many different types of cells – for example a blood stem cell can form both red blood cells (which carry oxygen) and white blood cells (which form your immune system).

But stem cells don’t just decide that they suddenly want to become a red blood cell overnight – they undergo a process of development via a series of intermediate stages, where they briefly exist as several subtly different types of cell along the way.

These intermediate cells, known as progenitors, are slippery characters. They exist extremely transiently and are enormously difficult to catch – but understanding how they work is critical, as many different diseases arise when stem cells don’t transition fully between progenitor stages.

Figure for Bryony

Cross section of the thymus showing the outer layer or cortex (Ctx) and inner compartment called the medulla (Med). Importantly, the white areas in the cortex and the pink areas in the medulla show distinct subsets of progenitor cells residing in different physical compartments within the thymus. Image credit: Buono et al., Nature Cell Biology (2016).

However, at the WIMM scientists working in Claus Nerlov’s and Sten Eirik Jacobsen’s groups have managed to do just that: to catch these elusive cells as they transition from stem cell to a fully developed, highly specialized cell type, and show how the physical environment in which these cells transiently exist is critical to their development.

The team, led by Mario Buono, was working on a subset of blood cells called T-cells, which form part of the immune system. Blood stem cells are found in the bone marrow, but T-cell progenitors (the intermediates between the stem cell and the fully fledged T-cell itself) are known to develop in the thymus – a small organ located in front of your heart, between your lungs.

Scientists already knew that immature progenitors went into the thymus, and fully specialized T-cells popped out. They also had an idea about the various different stages that the progenitors might pass through, and some of the chemicals that might be involved – but nobody knew which physical parts of the thymus itself were associated with each of the intermediate cells.

In this paper, the Nerlov lab show that different regions of the thymus physically associate with the different types of progenitor cells. Furthermore, the continued development of these progenitors to fully mature T-cells is dependent on the presence of a specific signal found on the surface of the cells in the thymus, called KitL.

When the scientists removed KitL from these specific cells in the thymus, the number of progenitor cells which were able to continue to develop to T-cells was dramatically reduced. Strikingly, removing KitL individually from different cell types within the thymus affected different stages of progenitor development. Therefore, the environment supporting T-cell development changes during the developmental process.

The concept that developing cells must be supported by a specific physical environment has been extensively analysed for stem cells themselves, but rarely looked at in detail for progenitor cells. This paper, one of the first to extensively characterize the highly dynamic environment within which these highly specialized cell types develop, represents a significant advance for the field.

The transient nature of progenitor cells has hindered attempts to study these elusive cells for decades – but Claus Nerlov’s team have found a way to catch them. The question now is whether other progenitors, not just T-cell progenitors, behave in the same way. Watch this space…

 

Post edited by Mario Buono, Claus Nerlov and Sten Eirik Jacobsen.

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