Blood Cell-Derived Microvesicles in Hematological Diseases and beyond

Abstract

Microvesicles or ectosomes represent a major type of extracellular vesicles that are formed by outward budding of the plasma membrane. Typically, they are bigger than exosomes but smaller than apoptotic vesicles, although they may overlap with both in size and content. Their release by cells is a means to dispose redundant, damaged, or dangerous material; to repair membrane lesions; and, primarily, to mediate intercellular communication. By participating in these vital activities, microvesicles may impact a wide array of cell processes and, consequently, changes in their concentration or components have been associated with several pathologies. Of note, microvesicles released by leukocytes, red blood cells, and platelets, which constitute the vast majority of plasma microvesicles, change under a plethora of diseases affecting not only the hematological, but also the nervous, cardiovascular, and urinary systems, among others. In fact, there is evidence that microvesicles released by blood cells are significant contributors towards pathophysiological states, having inflammatory and/or coagulation and/or immunomodulatory arms, by either promoting or inhibiting the relative disease phenotypes. Consequently, even though microvesicles are typically considered to have adverse links with disease prognosis, progression, or outcomes, not infrequently, they exert protective roles in the affected cells. Based on these functional relations, microvesicles might represent promising disease biomarkers with diagnostic, monitoring, and therapeutic applications, equally to the more thoroughly studied exosomes. In the current review, we provide a summary of the features of microvesicles released by blood cells and their potential implication in hematological and non-hematological diseases.

Keywords: blood; disease biomarker; extracellular vesicles; hematological disorder; medium/large vesicles; microparticles; microvesicles.

Figure 1

Immunophenotyping characteristics of blood cell-derived microvesicles. (1) RMVs characterized by the cell-specific marker CD235. PS acts as an “eat-me” signal and prothrombotic marker. The presence of human argonaute 1-micro ribonucleic acid antigen in MVs has been shown to be associated with innate resistance of RBCs to malaria infection, whereas TER-119 antigen has a cardioprotective effect. (2) PMVs are recognized by the platelet-specific markers, CD41 and CD61. They exert their hemostatic dynamics through their PS exposure and TF expression which can initiate the extrinsic coagulation pathway. Interleukin 1 beta and caspase-1 presence in PMVs can induce vasoocclusion is sickle cell disease whereas GPIb, GPIIb/IIIa, GPIX, and CD9 have been associated with calcification on acute coronary syndrome and constitute independent predictors for thrombotic and atherothrombotic events. (3) CD3, CD19, and CD11a levels on LMVs show strong correlation with inflammatory diseases (e.g., inflammatory autoimmune polymyositis/dermatomyositis) and are accumulated in the lipid-rich atherosclerotic plaques of familial hypercholesterolaemia patients. A range of ambiguous effects have been also proposed for LMVs on vascular homeostasis (CD11a) and neovascularization (sonic hedgehog protein). (4) aLMVs express CD44, Fas-L, CD11a, PS, and TF playing an important role on dendritic cells function, endothelial function impairment, vascular hyporeactivity induction, and in blood hemostasis. (5) Monocyte-derived MVs (MoMVs) have procoagulant activity via expression of the procoagulant proteins (TF and thrombomodulin) and PS on their surface. Moreover, MoMVs expressing CD14, CD18, and PS impact on endothelial cell dysfunction or damage (6) Neutrophil-derived microvesicles (NMVs) exposing PS on their outer membrane leaflet have been shown to activate the classic pathway of complement--. NMVs expressing active CD11b/CD18 integrin molecule, trigger platelet activation. miR-155 enriched NMVs induce cytokine release and MPO positive NMVs promote endothelial cells damage and vascular dysfunction. (7) Natural-killer-derived MVs (NKMVs) carry internal and surface molecules (e.g., perforin, granzymes, granulysin, CD40L, and miRNAs associated with anti-tumor activity) that can inhibit proliferation and induce apoptosis of tumor cell lines. RMVs, Red blood cell-derived microvesicles; MoMVs, Monocyte-derived microvesicles; PMVs, Platelet-derived microvesicles; NMVs, Neutrophil-derived microvesicles; LMVs, Lymphocyte-derived microvesicles; NKMVs, Natural Killer-derived microvesicles; aLMVs, Apoptotic Lymphocyte-derived microvesicles; CD235, glycophorin-A, PS; phosphatidylserine; TER-119, TER-119 antigen; CD14, lipopolysaccharide receptor; TF, Tissue factor; hAgo2-miRNA, Human argonaute 1- micro Ribonucleic acid (RNA); CD11b, Macrophage-1 antigen; CD18, Integrin beta chain-2; CD41, Integrin alpha chain 2b; IL-1β, Interleukin 1 beta; GPIIb/IIIa, Glycoprotein IIb/IIIa; CD9, a member of the transmembrane 4 superfamily; GPIX, Glycoprotein IX; GPIb, Glycoprotein Ib; miR-155, microRNA-155; CD66b, Glycosylphosphatidylinisotol (GPI)-anchored, highly glycosylated protein belonging to the carcinoembryonic Ag supergene family; MPO, Myeloperoxidase; CD3, T-cell surface antigen; CD19, B-lymphocyte antigen; CD45, Leukocyte common antigen; CD11a, integrin alpha L chain; CD52, CAMPATH-1 antigen; miRNA, microRNA; CD44, Homing cell adhesion molecule (HCAM); CD56, Neural cell adhesion molecule; CD16, FcγRIII.