Megakaryocyte-derived microvesicles, please stand up!

M icrovesicles (MVs), small circular membrane fragments shed from the cell surface or released from the endosomal compartment, play an important and underappreciated role in cell-to-cell communication.1 This intriguing MV-mediated communication system emerged very early during evolution and served as a template for the further development of cell-to-cell interaction mechanisms involving soluble bioactive mediators and finetuned ligand-receptor interactions. The biologic significance of MVs has been largely overlooked for many years, and MVs were regarded just as simple cellular debris/fragments or part of apoptotic bodies. However, evidence is accumulating that these tiny membrane fragments orchestrate several biologic responses. MVs contain numerous bioactive proteins and lipids similar to those present in the membranes of the cells from which they originate. Furthermore, since they engulf some cytoplasm during membrane blebbing, they may also contain proteins and mRNA.2 Thus, MVs may stimulate target cells directly by surface-expressed ligands acting as a kind of “signaling complex.” In addition, they may transfer surface receptors from one cell to another and deliver proteins, mRNA, bioactive lipids, and even whole organelles (eg, mitochondria) into target cells. Finally, they may also serve as a vehicle to transfer infectious particles between cells, such as prions or HIV (“Trojan horse” mechanism of infection). It is widely accepted that MVs circulating in peripheral blood originate from activated blood platelets, endothelial cells, and leukocytes. Platelet-derived microvesicles (PMVs) are released both from the platelet surface or from the endosomal compartments (exosomes) and, as shown in the figure, may (1) directly stimulate other cells (eg, hematopoietic cells, lymphocytes and endothelium),3 (2) transfer platelet expressed receptors (eg, CD41 or CXCR4)4,5 to the surface of other cells, and, in some situations, or (3) transfer mRNA, proteins, and even infectious particles (eg, prions, HIV) to the target cells. Interestingly, in healthy donors, the majority of circulating CD41 MVs do not express surface activation marker CD62P, suggesting that they do not originate from activated platelets. Here, Flaumenhaft et al report that a significant number of circulating CD41 MVs in healthy individuals are derived directly from megakaryocytes (Megs). In a sequence of very elegant studies, the authors first demonstrate this via electron microscopy of spontaneous MVs are shed from both megakaryocytes (MegMVs) and platelets (PMVs). Evidence suggests that MVs may (1) stimulate target cells directly by surface-expressed ligands acting as a kind of “signaling complex,” (2) transfer surface receptors from one cell to another (eg, CD41, CXCR4), or (3) deliver proteins, mRNA, bioactive lipids, and even serve as a vehicle (“Trojan horse” mechanism) to transfer infectious particles between cells (eg, prions).