In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

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Biological properties of extracellular vesicles and their physiological functions

Both eukaryotic and prokaryotic cells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles? Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Although this release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, for instance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulating that vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembrane receptors and genetic information. Because also bacteria communicate to each other via extracellular vesicles, the intercellular communication via extracellular cargo carriers seems to be conserved throughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economic manner of exchanging information between cells. Furthermore, vesicles protect cells from accumulation of waste or drugs, they contribute to physiology and pathology, and they have a myriad of potential clinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass the blood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately, pathways of vesicle release and vesicles themselves are also being used by tumors and infectious diseases to facilitate spreading, and to escape from immune surveillance. In this review, the different types, nomenclature, functions, and clinical relevance of vesicles will be discussed.

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Classification, Functions, and Clinical Relevance of Extracellular Vesicles

Nanomaterials hold promise as multifunctional diagnostic and therapeutic agents. However, the effective application of nanomaterials is hampered by limited understanding and control over their interactions with complex biological systems. When a nanomaterial enters a physiological environment, it rapidly adsorbs proteins forming what is known as the protein ‘corona’. The protein corona alters the size and interfacial composition of a nanomaterial, giving it a biological identity that is distinct from its synthetic identity. The biological identity determines the physiological response including signalling, kinetics, transport, accumulation, and toxicity. The structure and composition of the protein corona depends on the synthetic identity of the nanomaterial (size, shape, and composition), the nature of the physiological environment (blood, interstitial fluid, cell cytoplasm, etc.), and the duration of exposure. In this critical review, we discuss the formation of the protein corona, its structure and composition, and its influence on the physiological response. We also present an ‘adsorbome’ of 125 plasma proteins that are known to associate with nanomaterials. We further describe how the protein corona is related to the synthetic identity of a nanomaterial, and highlight efforts to control protein–nanomaterial interactions. We conclude by discussing gaps in the understanding of protein–nanomaterial interactions along with strategies to fill them (167 references).

Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment

Immune responses to implants – A review of the implications for the design of immunomodulatory biomaterials

THE purpose of this review is to evaluate recent developments in our understanding of the inflammatory response to cardiac surgery. Scientific knowledge in this field is continually expanding, potentially significant advances are regularly reported, and this area constitutes a major interface of clinical and basic scientific research. The review is divided into four major sections. The first section describes the pathophysiology of the inflammatory response to cardiac surgery. Factors that influence the extent of the inflammatory response, including the immunomodulatory effects of drugs commonly administered perioperatively, are discussed in the second section. The third section examines the evidence that the inflammatory response contributes to adverse perioperative events, in particular organ dysfunction, while the final section evaluates potential therapeutic strategies to control this response. The review concludes with a summary of potential future research directions and key deficiencies in our knowledge regarding the inflammatory response to cardiac surgery.

The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist.

Contact between blood and a biomaterial surface induces an immediate complement-mediated inflammatory response. Under these conditions, the alternative pathway of complement is often initiated and amplified on the biomaterial surface. Adsorption of a protein such as C3 to a polymer surface induces conformational changes in the protein. Based on the expression on adsorbed C3 of conformational neoepitopes specific for bound C3 fragments, we have hypothesized that adsorbed C3 is able to bind factor B and form a functional C3,Bb convertase. Using a quartz crystal microbalance to monitor binding of proteins to a polymer surface, we have demonstrated that a functional C3-containing alternative pathway convertase can be formed, in particular, in the presence of properdin. These data indicate that adsorption of C3 induces conformational changes that turn C3 into a C3b-like molecule that is able to participate in the functioning of the alternative convertase, and they suggest a new mechanism for complement activation on a biomaterial surface.

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C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase

Conformational changes of a model protein (complement factor 3) adsorbed on hydrophilic and hydrophobic solid surfaces

The subunit composition of human C3 and C5 was analyzed. Acrylamide gel electrophoresis of the fully reduced and dissociated proteins disclosed a similar structure, consisting of one α and one β subunit, linked together by one or more disulfide bonds. The approximate molecular weights for the α and β subunits of C3 as well as C5 were 140,000 and 80,000 respectively. caused cleavage solely of C3α, whereas trypsin affected both C3α as well as C3β. A characteristic subunit modification by both enzymes indicated that C3α constitutes the source of C3a. as well as typsin exclusively affect C5α. C5a therefore appears to originate from the C5α subunit. The mode of primary cleavage by and trypsin differs, giving rise to different forms of C5b. The question is raised if multiple forms of C5a also exist. It appeared from our studies that certain forms of C5b may retain portions of the α subunit, which could potentially release some biologically active split products following secondary cleavage by the appropriate enzyme.

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Human C3 and C5: subunit structure and modifications by trypsin and C42-C423.

https://www.annalsthoracicsurgery.org/article/0003-4975(94)92219-5/pdf

Complement activation during cardiopulmonary bypass: Effects of immobilized heparin☆

Immunocomplexes (IC) in serum were analyzed in 54 patients with subarachnoid hemorrhage (SAH) from ruptured arterial aneurysms. A previous study had shown that patients with SAH and vasospasm had a significantly higher incidence of ICs in the blood than patients without vasospasm. The aim of the present study was to study how the IC content varied with time and compare this pattern with the clinical picture. Forty-two patients presented clinical or radiological signs of cerebral vasospasm during their hospital stays, whereas 12 patients showed no such signs. The patients with vasospasm had a significantly higher amount of ICs in serum than those without vasospasm. In 37 patients with vasospasm, the changes of IC content during the 1st weeks after SAH correlated well with the clinical course. Data indicated that a high IC content preceded the onset of vasospasm and a low content preceded clinical improvement. This observation supports the idea that the presence of ICs might be the cause and not the result of vasospasm.

Ulf R. Nilsson

Papers

C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase

Conformational changes of a model protein (complement factor 3) adsorbed on hydrophilic and hydrophobic solid surfaces

Human C3 and C5: subunit structure and modifications by trypsin and C42-C423.

Complement activation during cardiopulmonary bypass: Effects of immobilized heparin☆

Serum immunocomplexes in patients with subarachnoid hemorrhage.