Rossella Crescitelli: What are exosomes and what can they do?

Rossella Crescitelli, Image Courtesy of Lonza

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First, what are exosomes, where do they come from, and what do they do? Dr Kat Arney investigates.

Kat: To put it simply, exosomes are tiny biological bags of ‘stuff’ produced by cells that can travel around the body. They’re one member of a much larger family of extracellular vesicles - a blanket term encompassing a wide variety of ‘bags’ with various components, sizes and functions. More specifically, exosomes are firmly in the category of nanoparticles, measuring an average of 100 nanometres in diameter, making them a hundredth of the diameter of a typical human cell and about 40 times the diameter of a strand of DNA. So, pretty small.

So small, in fact, that they were overlooked for many years. They were dismissed as little more than biological ‘dust’ sprinkled from blood clotting structures known as platelets when they were first spotted more than 50 years ago. Exosomes were formally named and recognised in the early 1980s, when researchers noticed that maturing red blood cells shed little packets of unwanted molecules. Back then, it was thought that exosomes were some kind of garbage disposal system, enabling cells to pack up and discard unwanted stuff.

Fast forward another decade or so to the mid-90s, and it starts to become clear that there might be more to exosomes than meets the eye, when researchers found that exosomes were involved in presenting proteins to immune cells to help train up our immune responses.

Over the next few years researchers start to discover more about exosomes. They’re shown to contain a mixture of the sames kinds of things that you’d find in a regular cell - DNA, RNA, proteins, fats and other chemicals - all wrapped up in the same kind of membrane that surrounds our cells, known as a lipid bilayer. They’re produced within cells from complex structures called multivesicular bodies, and eventually get popped out of the cell to go off around the body where they can be taken up by other cells. You can imagine them almost like a sample from inside the cell, wrapped up neatly in a biological mailbag and posted out into the world of the body.

Then came the real breakthrough, when scientists discovered that not only were exosomes packed with messenger RNA - the recipes encoded by our genes - which could be translated by recipient cells to make proteins, a bit like sending a favourite recipe through the post to a friend so they can make it too. It also turned out that exosomes contain various small RNAs, which help to switch genes off, raising the exciting possibility that they may be controlling gene activity in the cells that take them up. 

Since then, the field of exosome research has boomed, as the power of these little particles in cell communication becomes clearer. One particularly exciting area is in cancer research, as it looks like exosomes sent out by cancer cells can ‘prepare the ground’ for seeding secondary metastatic tumours in other parts of the body.

To find out more about exosomes and what they’re up to, I h ad a chat with Dr Rossella Crescitelli, a researcher at Sahlgrenska Center for Cancer Research in at the University of Gothenburg in Sweden, whose work focuses on studying these molecular mailbags. First, I wanted to know how they get around in the body? And how do they know where to go? Turns out, we’re not really sure.

Rossella: How they arrive to the cells, how they communicate, this is not well discovered. They contain a lot of proteins. If we think about white cells, they are able to recognise an antigen thanks to a receptor that these cells have. So the principle is more or less the same. They are surrounded by proteins, so there will be cells that will recognise these proteins and will keep the message that they bring.

Kat: So almost like you recognise, "I can lock onto this. This goes with me and I can go into that cell."

Rossella: Yeah. And this is in my opinion, the magic part, because they are different from other kinds of particles. They are recognised as 'self' by the cells. And probably for this reason, they have a really long half life in circulation. They can go through the brain barrier, for example, and we know that this is a big problem with drugs; it's really difficult for normal drugs to go through the brain barrier.

Rossella: They are able to pass it because they're recognised as 'self'. So this is why they have such a huge potential as drugs to cure disease.

Kat: But I guess then we need to work out, well, how do we harness that? How do we work out how to target an exosome, not only with the cargo that you want, but to go where you want. So I guess that is the big challenge now.

Rossella: Yeah. There are a lot of challenges to be honest. The potential is huge. I focus all my research on the very basic question in the exosome or extracellular vesicles field. One of the really, really basic questions is how many type of extracellular vesicles are in circulation.

Rossella: We know that there are a lot but we still don't know how many, and the big question is how can we distinguish them. The key point is to find a marker that is able to distinguish an extracellular vesicle released by one specific kind of cells from another one, for example, cancer cells.

Rossella: When we arrive at that point, and to be honest we are quite close to that, we will be able to fish out exactly those vesicles and use them as biomarkers for disease, or to load them with drugs and use them as a sort of shuttle. But in my opinion, the really key point is to find markers that are able to distinguish them.

Kat: Exosomes are produced naturally by many different cell types in the body. They were originally found in blood clotting structures to help the blood coagulate and stop a bleed. But exosomes also play a big role in cancer communication and help a tumour become metastatic and spread around the body?

So can we say whether exosomes are ‘goodies’ or ‘baddies’ in the body? I posed this question to Rossella…

Rossella: I mean, who can say? If you think about cancer, yeah, they are bad in a sense, but nothing is good or bad in biology. As with everything, the body can use one thing in a good way. For coagulation, we know that they are useful because we without proper coagulation we would die because we would lose a lot of blood.

Rossella: But when cells became cancer cells, they release exosomes and we know that they help the cells to become metastatic. So it's good and bad. In principle, they are good, but if the cell is a cancer cell, everything will then be bad.

Kat: I guess it is like any communication system, like email or Twitter. You can have good tweets and you can have bad tweets, and good emails and bad emails.

Rossella: Exactly. It's exactly like this. But as everything in biology, in my opinion, we are smart enough to use them in a good way. We can use the good points of them; that they are natural, so we don't have to manipulate them so much. We can use what they are able to do. We can use them if we load the drug that we want to spread out in the circulatory system.

Kat: What do you think is still the biggest mystery about exosomes? What are you really curious to find out?

Rossella: I want to know how they are so smart. How can they arrive exactly to that point, to those cells, and convey the message that they want just to those cells and not to others.

Rossella: In principle it's easy. They contain proteins, they're recognised by the cells: yes. But why do they reach just certain cell types and not other ones?

Kat: I bet you can't wait to find out.

Thanks to Rossella Crescitelli from the University of Gothenburg, Sweden.