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Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.

Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these.Extracellular vesicles (EVs) mediate cell–cell communication in physiology and pathology but many questions remain about the mechanisms governing their delivery to recipient cells. This Expert Recommendation article highlights areas of progress and challenges in establishing the importance of EV-mediated communication in vivo.

Cellular protrusions are highly dynamic structures that facilitate cell–cell communication and are increasingly recognised for their roles in the shedding of bioactive extracellular vesicles (EVs). The intrinsic and extrinsic mechanisms that govern the shedding of EVs from cellular protrusions and their potential physiological roles are beginning to emerge.This Comment draws attention to cellular protrusions as a source of extracellular vesicles (EVs). These protrusion-derived vesicles expand the repertoire of EVs, impacting current nomenclature and our understanding of EV functions in inter-cellular communication.

There is increasing evidence that secreted vesicles play important roles in numerous aspects of biology (e.g. intercellular vesicle traffic, immunity, development, neurobiology and microbiology), contribute to many human diseases (e.g. cancer, neurodegenerative disorders and HIV/AIDS) and have significant biotechnological potential. This expanding interest in extracellular vesicles has also highlighted some vexing problems related to their nomenclature. At the first meeting of the International Society for Extracellular Vesicles (ISEV) in Gothenburg, Sweden (April 2012), the authors chaired a session on the issue of vesicle nomenclature. Citation: Journal of Extracellular Vesicles 2013, 2: 20389 - http://dx.doi.org/10.3402/jev.v2i0.20389

Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.This Review describes the state of the art in imaging extracellular vesicles in animals to study their release, biodistribution and uptake, and covers labeling strategies, microscopy methods and discoveries made in model organisms.

Animals precisely control the morphology and assembly of guanine crystals to produce diverse optical phenomena in coloration and vision. However, little is known about how organisms regulate crystallization to produce optically useful morphologies which express highly reflective crystal faces. Guanine crystals form inside iridosome vesicles within chromatophore cells called iridophores. By following iridosome formation in developing scallop eyes, we show that pre-assembled, fibrillar sheets provide an interface for nucleation and direct the orientation of the guanine crystals. The macromolecular sheets cap the (100) faces of immature guanine crystals, inhibiting growth along the π-stacking growth direction. Crystal growth then occurs preferentially along the sheets to generate highly reflective plates. Despite their different physical properties, the morphogenesis of iridosomes bears a striking resemblance to melanosome morphogenesis in vertebrates, where amyloid sheets template melanin deposition. The common control mechanisms for melanin and guanine formation inspire new approaches for manipulating the morphologies and properties of molecular materials.

The biotin-reversible interaction between a 'hook' protein localized to a particular cellular compartment and a reporter protein of interest is exploited in a simple system to synchronize protein traffic through the secretory pathway. To dissect secretory traffic, we developed the retention using selective hooks (RUSH) system. RUSH is a two-state assay based on the reversible interaction of a hook protein fused to core streptavidin and stably anchored in the donor compartment with a reporter protein of interest fused to streptavidin-binding peptide (SBP). Biotin addition causes a synchronous release of the reporter from the hook. Using the RUSH system, we analyzed different transport characteristics of various Golgi and plasma membrane reporters at physiological temperature in living cells. Using dual-color simultaneous live-cell imaging of two cargos, we observed intra- and post-Golgi segregation of cargo traffic, consistent with observation in other systems. We show preliminarily that the RUSH system is usable for automated screening. The system should help increase the understanding of the mechanisms of trafficking and enable screens for molecules that perturb pathological protein transport.

Exocytic carriers convey neo-synthesized components from the Golgi apparatus to the cell surface. While the release and anterograde movement of Golgi-derived vesicles require the small GTPase RAB6, its effector ELKS promotes the targeting and docking of secretory vesicles to particular areas of the plasma membrane. Here, we show that specialized cell types exploit and divert the secretory pathway towards lysosome related organelles. In cultured melanocytes, the secretory route relies on RAB6 and ELKS to directly transport and dock Golgi-derived carriers to melanosomes. By delivering specific cargos, such as MART-1 and TYRP2/ DCT, the RAB6/ELKS-dependent secretory pathway controls the formation and maturation of melanosomes but also pigment synthesis. In addition, pigmentation defects are observed in RAB6 KO mice. Our data together reveal for the first time that the secretory pathway can be directed towards intracellular organelles of endosomal origin to ensure their biogenesis and function. The anterograde movement of Golgi-derived vesicles requires the small GTPase RAB6, while its effector ELKS targets these vesicles to particular areas of the plasma membrane. Here the authors show that RAB6 and ELKS function in the biogenesis of melanosome, demonstrating that the secretory pathway can be directed towards intracellular organelles of endosomal origin.

Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states. The activity of melanocytes determines skin pigmentation, and is regulated by a tight dialogue with keratinocytes. Here, the authors show that exosomes released by keratinocytes have a direct effect on melanocyte function, and exosome content is dependent on skin phototype and is modulated by ultraviolet B radiation.

Biological information can be shared between cells via extracellular vesicles. However, how cargo carried by extracellular vesicles elicits biological responses remains unresolved. Deciphering the molecular mechanisms that govern packaging and targeted delivery of extracellular vesicle cargo will be required to establish extracellular vesicles as important signalling entities.