Shedding New Light on Platelet Extracellular Vesicles in Sickle Cell Disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Middleton EA
PROVIDER: S-EPMC6938156 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Shedding New Light on Platelet Extracellular Vesicles in Sickle Cell Disease.
Middleton Elizabeth A EA Ware Lorraine B LB Rondina Matthew T MT
American journal of respiratory and critical care medicine 20200101 1
Similar Datasets
Project description:Rationale: Intraerythrocytic polymerization of Hb S promotes hemolysis and vasoocclusive events in the microvasculature of patients with sickle cell disease (SCD). Although platelet-neutrophil aggregate-dependent vasoocclusion is known to occur in the lung and contribute to acute chest syndrome, the etiological mechanisms that trigger acute chest syndrome are largely unknown.Objectives: To identify the innate immune mechanism that promotes platelet-neutrophil aggregate-dependent lung vasoocclusion and injury in SCD.Methods: In vivo imaging of the lung in transgenic humanized SCD mice and in vitro imaging of SCD patient blood flowing through a microfluidic system was performed. SCD mice were systemically challenged with nanogram quantities of LPS to trigger lung vasoocclusion.Measurements and Main Results: Platelet-inflammasome activation led to generation of IL-1β and caspase-1-carrying platelet extracellular vesicles (EVs) that bind to neutrophils and promote platelet-neutrophil aggregation in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. The inflammasome activation, platelet EV generation, and platelet-neutrophil aggregation were enhanced by the presence of LPS at a nanogram dose in SCD but not control human blood. Inhibition of the inflammasome effector caspase-1 or IL-1β pathway attenuated platelet EV generation, prevented platelet-neutrophil aggregation, and restored microvascular blood flow in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro.Conclusions: These results are the first to identify that platelet-inflammasome-dependent shedding of IL-1β and caspase-1-carrying platelet EVs promote lung vasoocclusion in SCD. The current findings also highlight the therapeutic potential of targeting the platelet-inflammasome-dependent innate immune pathway to prevent acute chest syndrome.
| S-EPMC6938158 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-06-20 | E-GEOD-41575 | biostudies-arrayexpress
Project description:For many decades, the proper functioning of the human body has become a leading scientific topic. In the course of numerous experiments, a striking impact of probiotics on the human body has been documented, including maintaining the physiological balance of endogenous microorganisms, regulating the functioning of the immune system, enhancing the digestive properties of the host, and preventing or alleviating the course of many diseases. Recent research, especially from the last decade, shows that this health-benefiting activity of probiotics is largely conditioned by the production of extracellular vesicles. Although the importance of extracellular vesicles in the virulence of many live-threatening pathogens is widely described in the literature, much less is known with respect to the health-promoting effect of extracellular vesicles secreted by non-pathogenic microorganisms, including probiotics. Based on this, in the current review article, we decided to collect the latest literature data on the health-inducing properties of extracellular vesicles secreted by probiotics. The characteristics of probiotics' extracellular vesicles will be extended by the description of their physicochemical properties and the proteome in connection with the biological activities exhibited by these structures.
| S-EPMC9967243 | biostudies-literature
Project description:We previously found that the plasma of patients with sickle cell disease (SCD) contains large numbers of small extracellular vesicles (EVs) and that the EVs disrupt the integrity of endothelial cell monolayers (especially if obtained during episodes of acute chest syndrome, ACS). The present study was designed to test the generality of this finding to other complications of SCD, specifically to evaluate the possibility that circulating EVs isolated during a vaso-occlusive crises (VOC) also cause damage to the intercellular connections between endothelial cells. Plasma was obtained from nine pediatric subjects at baseline and during VOC episodes. EVs isolated from these samples were added to cultures of microvascular endothelial cells. Immunofluorescence microscopy was employed to assess monolayer integrity and to localize two intercellular junction proteins (VE-cadherin and connexin43). The EVs isolated during VOC caused significantly greater monolayer disruption than those isolated at baseline. The extent of disruption varied between different episodes of VOC or ACS in the same patient. The VOC EVs disrupted the integrity of both junction proteins at appositional membranes. These results suggest that circulating EVs may be involved in modulating endothelial integrity contributing to the pathogenesis of different complications of SCD.
| S-EPMC8836895 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-06-20 | GSE41575 | GEO
Project description:BackgroundPlatelet (Plt)-derived extracellular vesicles (Plt-EVs) have hemostatic properties similar to Plts. In addition to hemostasis, Plts also function to stabilize the vasculature and maintain endothelial cell (EC) barrier integrity. We hypothesized that Plt-EVs would inhibit vascular EC permeability, similar to fresh Plts. To investigate this hypothesis, we used in vitro and in vivo models of vascular endothelial compromise and bleeding.MethodsIn the vitro model, Plt-EVs were isolated by ultracentrifugation and characterized for Plt markers and particle size distribution. Effects of Plts and Plt-EVs on endothelial barrier function were assessed by transendothelial electrical resistance measurements and histological analysis of endothelial junction proteins. Hemostatic potential of Plt-EVs and Plts was assessed by multiple electrode Plt aggregometry. Using an in vivo model, the effects of Plts and Plt-EVs on vascular permeability and bleeding were assessed in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice by an established Miles assay of vascular permeability and a tail snip bleeding assay.ResultsIn the in vitro model, Plt-EVs displayed exosomal size distribution and expressed Plt-specific surface markers. Platelets and Plt-EVs decreased EC permeability and restored EC junctions after thrombin challenge. Multiplate aggregometry revealed that Plt-EVs enhanced thrombin receptor-activating peptide-mediated aggregation of whole blood, whereas Plts enhanced thrombin receptor-activating peptide-, arachidonic acid-, collagen-, and adenosine diphosphate-mediated aggregation. In the in vivo model, Plt-EVs are equivalent to Plts in attenuating vascular endothelial growth factor (VEGF)-A-induced vascular permeability and uncontrolled blood loss in a tail snip hemorrhage model.ConclusionOur study is the first to report that Plt-EVs might provide a feasible product for transfusion in trauma patients to attenuate bleeding, inhibit vascular permeability, and mitigate the endotheliopathy of trauma.
| S-EPMC7381393 | biostudies-literature
Project description:Extracellular vesicles (EVs) are mediators of cell communication during health and disease, and abundantly released by platelets upon activation or during ageing. Platelet EVs exert modulatory effects on immune and vascular cells. Platelet EVs may modulate the function of vascular smooth muscle cells (SMC). Platelet EVs were isolated from platelet-rich plasma and incubated with SMC in order to assess binding, proliferation, migration and pro-inflammatory phenotype of the cells. Platelet EVs firmly bound to resting SMC through the platelet integrin αIIbβ3, while binding also occurred in a CX3CL1-CX3CR1-dependent manner after cytokine stimulation. Platelet EVs increased SMC migration comparable to platelet derived growth factor or platelet factor 4 and induced SMC proliferation, which relied on CD40- and P-selectin interactions. Flow-resistant monocyte adhesion to platelet EV-treated SMC was increased compared with resting SMC. Again, this adhesion depended on integrin αIIbβ3 and P-selectin, and to a lesser extent on CD40 and CX3CR1. Treatment of SMC with platelet EVs induced interleukin 6 secretion. Finally, platelet EVs induced a synthetic SMC morphology and decreased calponin expression. Collectively, these data indicate that platelet EVs exert a strong immunomodulatory activity on SMC. In particular, platelet EVs induce a switch towards a pro-inflammatory phenotype, stimulating vascular remodelling.
| S-EPMC5505004 | biostudies-literature
Project description:BackgroundNeurofilament light chain (NfL) is essential for axonal maintenance and reflects neuronal damage. Extracellular vesicles (EVs), especially exosomes, secreted by cells into the blood, are emerging as novel biomedical research platforms of physiological and pathological processes. The present study investigated the possible association between plasma EV NfL and Parkinson's disease (PD).MethodsOne hundred and sixteen patients with mild to moderate PD and 46 non-PD, neurological controls were recruited, and their clinical motor symptoms and cognitive function were evaluated. Plasma EVs were isolated using an exoEasy kit, and immunomagnetic reduction assay was used to assess EV NfL level. Statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant.ResultsThe isolated plasma EVs were validated according to size and the presence of specific surface markers. Compared with the neurological control group, the levels of plasma EV NfL in patients with PD were not significantly different (PD: 9.42 ± 3.89, control: 9.53 ± 3.62 pg/mL plasma, p = 0.71). On the other hand, plasma EV NfL in patients with PD trendwise correlated with the severity of akinetic rigidity (p = 0.05). PD patients with optimal EV NfL (lowest quartile) had 6.66 ± 2.08 lower Unified Parkinson's Disease Rating Scale-III score after adjustment for age, sex, and disease duration.ConclusionPlasma EV NfL levels did not distinguish patients with PD from the neurological control group. The possible correlation between plasma EV NfL with the severity of motor symptoms within the PD patients, especially with akinetic rigidity, was noted. Further clinical validation of the blood EV NfL by a longitudinal follow-up study of PD patients is warranted.
| S-EPMC7724268 | biostudies-literature
Project description:Tendon injuries represent over 30-50% of musculoskeletal disorders worldwide, yet the available therapies do not provide complete tendon repair/regeneration and full functionality restoring. Extracellular vesicles (EVs), membrane-enclosed nanoparticles, have emerged as the next breakthrough in tissue engineering and regenerative medicine to promote endogenous tissue regeneration. Here, we developed a 3D human in vitro model mimicking the signature of pathological tendon and used it to evaluate the influence that different platelet-derived EVs might have in tendon tissue repair mechanisms. For this, different EV populations isolated from platelets, small EVs (sEVs) and medium EVs (mEVs), were added to the culture media of human tendon-derived cells (hTDCs) cultured on isotropic nanofibrous scaffolds. The platelet-derived EVs increased the expression of tenogenic markers, promoted a healthy extracellular matrix (ECM) remodeling, and the synthesis of anti-inflammatory mediators. These findings suggest that platelet EVs provided relevant biochemical cues that potentiated a recovery of hTDCs phenotype from a diseased to a healthy state. Thus, this study opens new perspectives for the translation of platelet-derived EVs as therapeutics.
| S-EPMC8954460 | biostudies-literature
Project description:Extracellular vesicles (EVs) are emerging as key players in intercellular communication. EVs can transfer biological macromolecules to recipient cells, modulating various physiological and pathological processes. It has been shown that tumor cells secrete large amounts of EVs that can be taken up by malignant and stromal cells, dictating tumor progression. In this study, we investigated whether EVs secreted by melanoma cells in response to chemotherapy modulate tumor response to alkylating drugs. Our findings showed that human and murine melanoma cells secrete more EVs after treatment with temozolomide and cisplatin. We observed that EVs shed by melanoma cells after temozolomide treatment modify macrophage phenotype by skewing macrophage activation towards the M2 phenotype through upregulation of M2-marker genes. Moreover, these EVs were able to favor melanoma re-growth in vivo, which was accompanied by an increase in Arginase 1 and IL10 gene expression levels by stromal cells and an increase in genes related to DNA repair, cell survival and stemness in tumor cells. Taken together, this study suggests that EVs shed by tumor cells in response to chemotherapy promote tumor repopulation and treatment failure through cellular reprogramming in melanoma cells.
| S-EPMC6785560 | biostudies-literature