Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 2/2016, s. 132-136
*Anna Stachurska
Możliwe znaczenie diagnostyczne mikrocząstek błon komórkowych
Possible diagnostic role of cell membrane microparticles
Department of Immunohaematology, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Jadwiga Fabijańska-Mitek, PhD, Associate Professor
Streszczenie
Mikropęcherzyki (egzosomy i ektosomy) są heterogenną grupą sferycznych błonowych struktur uwalnianych przez większość komórek. Wydzielane są z błon komórkowych podczas dojrzewania i starzenia komórek. Te struktury błonowe wykrywane są m.in. w moczu, we krwi, w płynie owodniowym i ślinie. Aktywacja komórek indukowana przez różne czynniki powoduje wzrost wydzielania pęcherzyków. Funkcja tych struktur, skład i specyficzna ekspresja markerów powierzchniowych zależą od typu komórki, z której powstają. Artykuł przedstawia najnowszy stan wiedzy dotyczącej ogólnej charakterystyki, klasyfikacji, metod badawczych i roli struktur błonowych w różnych chorobach. Mikropęcherzyki jako biomarkery, czynniki pośredniczące w oddziaływaniach międzykomórkowych oraz nośniki białek mogą mieć zastosowanie w diagnostyce i prognozowaniu wielu chorób, np.: choroby sercowo-naczyniowe, autoimmunologiczne, cukrzyca, zakażenia i progresja nowotworowa. Określenie pochodzenia i liczby krążących mikropęcherzyków ułatwia wyjaśnienie ich udziału w patogenezie różnych schorzeń. Wyjaśnienie biologii oraz powstawania pęcherzyków jest istotne w zrozumieniu ich roli w warunkach prawidłowych oraz w rozmaitych chorobach. Pomimo stosowanych kilku metod (cytometria przepływowa, mikroskopia, ELISA), dokładny mechanizm, jak również czynniki biorące udział w tworzeniu pęcherzyków są tylko częściowo wyjaśnione i wymagają dalszych badań.
Summary
Extracellular vesicles (exosomes and ectosomes) are heterogenous group of spherical membrane structures released by most cells. They are secreted from the cell membranes during maturation and aging of cells. These membrane structures were detected, among others, in urine, blood, amniotic fluid and saliva. Cell activation, induced by various factors results in increased secretion of vesicles. These structures function, composition and their specific surface markers expression, depend on the cell type origin, from which they are formed. The article presents an overview of current knowledge on vesicle general characteristics, classification, research methods and role of membrane structures in various diseases. Microvesicles as biomarkers, mediators in cell interactions and proteins transporters can be applied in the diagnostics and prognosis of many diseases including cardiovascular, autoimmune, diabetes, infectious diseases and cancer metastasis. Determining the origin and the number of circulating microparticles facilitates explanation of their participation in the pathogenesis of various disorders. The elucidation of the biology and vesicles formation is important for understanding of their role in health and various disorders. Despite different applied methods (flow cytometry, microscopy, ELISA), the exact mechanism and components of the vesicle involved process formation remain only partially established and requires further studies.
General characteristics of vesicles
Extracellular vesicles (EV) are spherical membrane structures released by different types of normal and also cancer cells (1). The best known example are the vesicles derived from blood platelets (2). These membrane structures were detected, among others, in urine, blood, amniotic fluid, saliva, or semen. Under physiological conditions they are released from the cell membranes during maturation and aging of cells. Cell activation, induced by various factors (complement proteins, cytokines, stress factors), results in increased secretion of these structures. Recently involvement of vesicles in many diseases, including cardiovascular, autoimmune, diabetes, infectious diseases and cancer metastasis was studied (3). Determining the origin and the number of circulating microparticles facilitates explanation of their participation in the pathogenesis of various disorders. A few publications have revealed an increased release of these structures during long-term storage of blood for transfusions (4-8).
History of vesicles studies
First report concerning the vesicles was published in 1967 and has been described by Wolf. The author termed the structures “platelet dust”, the presence of which he found in human blood plasma. Structures secreted by activated blood platelets showed prothrombotic properties, owing to the presence of tissue factor – thrombospondin (9). The vesicles were isolated by ultracentrifugation, and observed by the electron microscopy. Discovery of the “platelet dust” marked the beginning of a new era regarding microvesicles formation and their role in the organism. Afterwards first publications on microvesicles released from erythrocytes (10), monocytes (11) and endothelial cells were published (12).
Microvesicles classification
The membrane vesicles are a heterogeneous group of different sizes, origin, biological and physical properties, mechanism and source of formation. Due to the size and origin, the vesicles were divided into: smaller exosomes, with a diameter of 30-100 nm, and bigger, ectosomes, measuring from 0.1 to 1 μm (13). Previous nomenclature of these structures was based on the origin of the cells, from which they are formed. In recent years terminology was based on the mechanism of their formation. Consensus on terminology and classification of vesicles was obtained in 2013 (14). Among the vesicles, the exosomes generated within the multivesicular bodies (MVBs) were separated. During the fusion of MVBs with the intraluminal membrane, vesicles are secreted from cells. After that, their size ranges from 40 to 150 nm. Major markers are tetraspanins (CD9, CD63, CD81, CD82), and markers of lipid rafts: flotillins 1 and 2. Other markers, such as heat shock proteins (HSP), MHC molecules, various components of endosomal sorting complex required for transport (ESCRT) and member of the Ras superfamily of monomeric G proteins (Rab) are used to identify these vesicles (15, 16).
The exosomes are formed and maturate in the intracellular (endosomal) vesicles. Afterwards they are secreted out of the cell by the fusion of vesicle membrane with the cell membrane, what involves soluble N-ethylmaleimide – sensitive factor attachment receptor transmembrane proteins (SNARE). In the process of exosome formation, Ca2+ dependent, vesicle associated membrane proteins (VAMP) are included. It was shown that in leukemia cells, the VAMP-7 protein plays an important role in the formation of exosomes during their fusion with the cell membrane. VAMP-1,-2,-3 proteins were identified in the exosomes secreted from tumor cells (13). Recent studies have shown that there are 2 types of exosomes: immunologically active exosomes that are involved in antigen presentation and costimulation and those containing RNA and mediating the genetic communication between cells (17).
Ectosomes are formed extracellularly, directly from the cell membrane by blebbing. The vesicle detachment occurs due to the contraction of cell, and then peeling it in specific sites. On the cell surface, the buds are formed, which mechanism involves active participation of cytoskeleton proteins e.g. actin. In the cell membrane proteins and lipids many changes take place. Similarly to the apoptosis, disruption of phospholipid asymmetry appears. In the cell membrane movement of phospholipids: phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin takes place with the participation of flippase, floppase and scramblase. Ca2+ ions play an important role during the formation of microvesicles. As a result, the increased concentration of Ca2+ activates enzymes, such as gelsolin, aminophospholipid translocase, floppase, scramblase and calpain, resulting in the change of cell membrane asymmetry (18). Exposure of phosphatidylserine on the outside layer of the plasma membrane seems to be one of the main microvesicle properties, although there are also microvesicles without exposed phosphatidylserine. RhoA protein, belonging to the family of small guanosine-5’-triphosphates (GTPases), Rho-activated protein kinases (ROCK) and actin-binding (LIM) kinases are regulators of ectosome secretion. Other regulator, is calpain – Ca2+ dependent enzyme, which participates in the regulation of cytoskeleton proteins, where it plays a significant role in the ectosome formation. Furthermore it was also concluded that the ADP-ribosylation factor 6 (ARF6) protein is essential both in these structure formation and secretion (13).
Surface markers

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otrzymano: 2016-01-04
zaakceptowano do druku: 2016-01-29

Adres do korespondencji:
*Anna Stachurska
Department of Immunohaematology Centre of Postgraduate Medical Education
ul. Marymoncka 99/103, 01-813 Warszawa
tel. +48 (22) 569-38-23
immunohematologia@cmkp.edu.pl

Postępy Nauk Medycznych 2/2016
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