Circulating Extracellular Vesicles and Endothelial Damage in Sickle Cell Disease

Lapping-Carr, Gabrielle; Gemel, Joanna; Mao, Yifan; Beyer, Eric C.

doi:10.3389/fphys.2020.01063

Cited by 18 publications

(15 citation statements)

References 68 publications

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“…EV pellets were resuspended in a final volume of 50 µL of phosphate buffered saline, pH 7.4 (PBS). Nanoparticle tracking analysis was performed using the Nanosight NS300 (Malvern Panalytical Inc., Westborough, MA, USA), as we have done previously [ 13 ]. Isolated EVs were diluted with PBS (1:100–1:150) and injected into the 488 nm laser chamber with a constant output controlled by a syringe pump.…”

Section: Methodsmentioning

confidence: 99%

“…EVs that encounter endothelial cells can affect their behavior through interactions at the cell surface or by the transfer of their contents (including proteins, lipids, DNA, mRNA, and microRNAs) that carry signals from their cell of origin. Plasma EVs may contribute to various vascular diseases (including SCD) by influencing key pathophysiologic components: Endothelial dysfunction and damage, ischemia-reperfusion injury, thrombosis, and inflammation (reviewed by [ 12 , 13 ]).…”

Section: Introductionmentioning

confidence: 99%

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Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome

Gemel

Mao

Lapping-Carr

et al. 2020

IJMS

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Intercellular junctions maintain the integrity of the endothelium. We previously found that the adherens and tight junctions between endothelial cells are disrupted by plasma extracellular vesicles from patients with sickle cell disease (especially those with Acute Chest Syndrome). In the current study, we evaluated the effects of these vesicles on endothelial gap junctions. The vesicles from sickle cell patients (isolated during episodes of Acute Chest Syndrome) disrupted gap junction structures earlier and more severely than the other classes of intercellular junctions (as detected by immunofluorescence). These vesicles were much more potent than those isolated at baseline from the same subject. The treatment of endothelial cells with these vesicles led to reduced levels of connexin43 mRNA and protein. These vesicles severely reduced intercellular communication (transfer of microinjected Neurobiotin). Our data suggest a hierarchy of progressive disruption of different intercellular connections between endothelial cells by circulating extracellular vesicles that may contribute to the pathophysiology of the endothelial disturbances in sickle cell disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome

Gemel

Mao

Lapping-Carr

et al. 2020

IJMS

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“…Nader et al . ( 97 ) and others ( 98 , 99 ) have reviewed the existing literature on microparticles and SCD. Generated primarily from RBCs and platelets, the number of microparticles is significantly higher in people with SCD compared with healthy controls, and these numbers increase further with increasing degrees of hemolysis and with vaso-occlusion.…”

Section: Characteristic Of Cell Subsets As Related To Alloimmunizatiomentioning

confidence: 99%

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Hendrickson¹

2020

Ann Blood

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The high prevalence of red blood cell (RBC) alloantibodies in people with sickle cell disease (SCD) cannot be debated. Why people with SCD are so likely to form RBC alloantibodies, however, remains poorly understood. Over the past decade, a better understanding of non-ABO blood group antigen variants has emerged; RH genetic diversity and the role this diversity plays in RBC alloimmunization is discussed elsewhere. Outside of antigen variants, the immune systems of people with SCD are known to be different than those of people without SCD. Some of these differences are due to effects of free heme, whereas others are impacted by hyposplenism. Descriptive studies of differences in white blood cell (WBC) subsets, platelet counts and function, and complement activation between people with SCD and race-matched controls exist. Studies comparing the immune systems of alloimmunized people with SCD to non-alloimmunized people with SCD to race-matched controls without SCD have uncovered differences in T-cell subsets, monocytes, Fcγ receptor polymorphisms, and responses to free heme. Studies in murine models have documented the role that recipient inflammation plays in RBC alloantibody formation, with human studies reporting a similar association. Murine studies have also reported the importance of type 1 interferon (IFNα/β), known to play a pivotal role in autoimmunity, in RBC alloantibody formation. The goal of this manuscript is to review existing data on factors influencing RBC alloantibody induction in people with SCD with a focus on inflammation and other immune system considerations, from the bench to the bedside.

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“…During hypoxia, proteins that are packed in RBC EVs are involved in nitric oxide production, which leads to increased vasodilation and smooth muscle cell relaxation [ 11 ]. Exosomes were found to be involved in hepcidin regulation in the context of βT [ 12 ], and EVs were found to induce endothelial damage in sickle cell disease [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle MicroRNA That Are Involved in β-Thalassemia Complications

Levin

Koren

Rebibo-Sabbah

et al. 2021

IJMS

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Beta thalassemia major (βT) is a hereditary anemia characterized by transfusion-dependency, lifelong requirement of chelation, and organ dysfunction. MicroRNA (miRNA) can be packed into extracellular vesicles (EVs) that carry them to target cells. We explored EV-miRNA in βT and their pathophysiologic role. Circulating EVs were isolated from 35 βT-patients and 15 controls. EV miRNA was evaluated by nano-string technology and real-time quantitative polymerase chain reaction (RT-qPCR). We explored effects of EVs on cell culture proliferation, apoptosis, and signal transduction. Higher amounts of small EV (exosomes) were found in patients than in controls. The expression of 21 miRNA was > two-fold higher, and of 17 miRNA < three-fold lower in βT-EVs than control-EVs. RT-qPCR confirmed differential expression of six miRNAs in βT, particularly miR-144-3p, a regulator of erythropoiesis. Exposure of endothelial, liver Huh7, and pancreatic 1.1B4 cells to βT-EVs significantly reduced cell viability and increased cell apoptosis. βT-EV-induced endothelial cell apoptosis involved the MAPK/JNK signal-transduction pathway. In contrast, splenectomized βT-EVs induced proliferation of bone marrow mesenchymal stem cells (BM-MSC). In summary, the miR-144-3p was strongly increased; βT-EVs induced apoptosis and decreased endothelial, pancreatic, and liver cell survival while supporting BM-MSC proliferation. These mechanisms may contribute to βT organ dysfunction and complications.

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Circulating Extracellular Vesicles and Endothelial Damage in Sickle Cell Disease

Cited by 18 publications

References 68 publications

Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome

Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Extracellular Vesicle MicroRNA That Are Involved in β-Thalassemia Complications

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