Revisiting the road to the discovery of exosomes

A look-back in time is presented to review the ‘Alice in Blunderland’ approach which led to the discovery of exosomes in and their extrusion from maturing reticulocytes. The key experiments which established that these structures are naturally occurring in both nucleated and non-nucleated reticulocytes are reviewed. The protein content of reticulocyte exosomes is largely that of plasma membrane proteins which are known to diminish in the course of reticulocyte maturation. Thus their protein content may vary depending on the species origin of the reticulocyte. To date, all exosomes also contain HSP 70, a major cellular chaperone which is not transmembrane bound. Significantly, the proteins externalized are intact and retain catalytic activity as well as native ligand binding activity. Their fate remains unknown.