Exosomes: History and Future Directions

Ms. Shalmali Pendse SIU-JRF

Exosomes, small spherical shaped vesicles (50 to 150nm in size) are secreted by almost all types of cells in the body, and thus, are found in the body fluids. Currently, studies on exosomes form a hot topic of research in the field of intercellular communication.

Around 30 years ago, in 1980’s, a scientist named C.V. Harding, then MD / Ph.D. student, focused on the study of pathways of receptor-mediated endocytosis for his Ph.D. thesis. In the study, he used rat reticulocytes or maturing blood cells as his model system because these cells were known to be abundant with transferrin receptors. During the maturation process, the reticulocytes lose the transferrin receptor. To visualize this, he incubated reticulocytes with gold-conjugated transferrin (AuTf) and observed that these AuTf particles are easily internalized by the reticulocytes. These internalized AuTf particles were located in many small vesicles present in the multi-vesicular bodies, thus, he chose to call them as multi-vesicular endosomes (MVE). After performing electron microscopy, he noticed that these MVE containing tranferrin receptors conjugated with AuTf particles fuse with plasma membrane and are discarded outside the cell. These observations revealed a novel mechanism for the loss of transferrin receptors during maturation of reticulocytes.

Previous to this discovery, these vesicles were thought to be garbage bags of the cells and were considered to be used by the cells to discard the unwanted material. Later in 1996, Raposo discovered that immune cells such as B lymphocytes also secreted exosomes, and they carried membrane-bound molecules essential for the adaptive immune response. Two years later, further research demonstrated that the dendritic cells also secrete exosomes and these exosomes carry functional immune agents that could promote induction of antitumor responses in mice. These results formed the basis for the hypothesis that exosomes could play active roles in intercellular communication, and thus, their potency in clinical applications.

Later in 2007, a group led by Jan Lötvall in Sweden discovered that exosomes harbor mRNAs and microRNAs. In vitro experiments also suggested that these mRNAs could be translated into proteins in the target cells, providing the first demonstration of genetic information transfer via exosomes, thus confirming their role in intercellular communication. This study triggered the exosome research around the world and different groups came up with the proof of exosomes being exploited by normal as well as tumor cells as messengers.

The current challenges in the exosomes field are mainly the technical difficulties in isolating pure population of exosomes and also getting better yield of exosomes due of which the data generated are not homogenous across globe. Also the signaling pathways responsible for the intercellular communication are still unexplored. Identification of various macromolecules present in the exosomes and the signaling pathways activated by them in the recipient cells will give basic understanding about the mechanism underlying this paracrine functioning of the cells.