Researchers here note a novel mechanism by which exosomes might cause issues following a stroke. Exosomes are a form of intracellular communication, membrane-bound packages of molecules that are released and taken up by cells in large numbers. Researchers are usually concerned with the way in which exosome cargo affects the behavior of cells once the exosomes are taken up, but here they note changes in exosome structure following a stroke that leads them to clump and block blood vessels. This is an interesting mechanism, and it will be equally interesting to see how the research community chooses to try to address it.
Researchers have found that after stroke, exosomes - nanosized biological suitcases packed with an assortment of cargo that cells swap, like proteins and fats - traveling in the blood get activated and sticky and start accumulating on the lining of blood vessels. Like a catastrophic freeway pileup, platelets, also tiny cells that enable our blood to clot after an injury, start adhering to the now-sticky exosomes, causing a buildup that can effectively form another clot, further obstruct blood flow to the brain and cause additional destruction.
One thing traveling exosomes typically aren't is sticky. Rather, much like our real suitcases, they have a smooth label that marks their intended destination. But when these external destination tags become inexplicably sticky following a stroke, not only do exosomes not reach their destination, they can worsen stroke outcome. In a bit of a perfect storm, the scientists have shown in both stroke models and human blood vessels that exosomes cruising through the blood then pick up RGD, the unique and normally sticky peptide sequence, arginine-glycine-aspartate, which is key to the pileup that can cause additional brain damage.
More typically, exosomes carry a negligible amount of RGD, a protein that's important in holding together the extracellular matrix that helps cells connect and form tissue. In the aftermath of a stroke, cells and the extracellular matrix both get damaged, and sticky RGD is effectively set free. Platelets normally aren't exposed to RGD, which should mostly be sequestered in the extracellular matrix, so they become angry, activated and also sticky in response.
Another piece of this sticky situation is that a receptor called αvβ3. Avβ3 also is found on the lining of blood vessels and naturally binds to sticky RGD as part of its role with the extracellular matrix. The new stroke study shows the RGD carrying exosomes also target these receptors. In fact, when scientists gave antibodies to αvβ3, the binding to the blood vessel lining was blocked. A bottom line of the new work is that RGD sequences are a key contributor to the secondary damage from stroke.