CD39 abrogates platelet-derived factors induced IL-1ß expression in the human placenta.

Tissue insults in response to inflammation, hypoxia and ischemia are accompanied by the release of ATP into the extracellular space. There, ATP modulates several pathological processes, including chemotaxis, inflammasome induction and platelet activation. ATP hydrolysis is significantly enhanced in human pregnancy, suggesting that increased conversion of extracellular ATP is an important anti-inflammatory process in preventing exaggerated inflammation, platelet activation and hemostasis in gestation. Extracellular ATP is converted into AMP, and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. Here, we aimed to elucidate developmental changes of placental CD39 and CD73 over gestation, compared their expression in placental tissue from patients with preeclampsia and healthy controls, and analyzed their regulation in response to platelet-derived factors and different oxygen conditions in placental explants as well as the trophoblast cell line BeWo. Linear regression analysis showed a significant increase in placental CD39 expression, while at the same time CD73 levels declined at term of pregnancy. Neither maternal smoking during first trimester, fetal sex, maternal age, nor maternal BMI revealed any effects on placental CD39 and CD73 expression. Immunohistochemistry detected both, CD39 and CD73, predominantly in the syncytiotrophoblast layer. Placental CD39 and CD73 expression were significantly increased in pregnancies complicated with preeclampsia, when compared to controls. Cultivation of placental explants under different oxygen conditions had no effect on the ectonucleotidases, whereas presence of platelet releasate from pregnant women led to deregulated CD39 expression. Overexpression of recombinant human CD39 in BeWo cells decreased extracellular ATP levels after culture in presence of platelet-derived factors. Moreover, platelet-derived factors-induced upregulation of the pro-inflammatory cytokine, interleukin-1ß, was abolished by CD39 overexpression. Our study shows that placental CD39 is upregulated in preeclampsia, suggesting an increasing demand for extracellular ATP hydrolysis at the utero-placental interface. Increased placental CD39 in response to platelet-derived factors may lead to enhanced conversion of extracellular ATP levels, which in turn could represent an important anti-coagulant defense mechanism of the placenta.

Platelet-derived factors dysregulate placental sphingosine-1-phosphate receptor 2 in human trophoblasts.

RESEARCH QUESTION: Sphingosine-1-phosphate (S1P) is an essential and bioactive sphingolipid with various functions, which acts through five different G-protein-coupled receptors (S1PR1-5). What is the localization of S1PR1-S1PR3 in the human placenta and what is the effect of different flow rates, various oxygen concentrations and platelet-derived factors on the expression profile of S1PR in trophoblasts? DESIGN: Expression dynamics of placental S1PR1-S1PR3 were determined in human first trimester (n = 10), pre-term (n = 9) and term (n = 10) cases. Furthermore, the study investigated the expression of these receptors in different primary cell types isolated from human placenta, verified the findings with publicly available single-cell RNA-Seq data from first trimester and immunostaining of human first trimester and term placentas. The study also tested whether the placental S1PR subtypes are dysregulated in differentiated BeWo cells under different flow rates, different oxygen concentrations or in the presence of platelet-derived factors. RESULTS: Quantitative polymerase chain reaction revealed that S1PR2 is the predominant placental S1PR in the first trimester and reduces towards term (P < 0.0001). S1PR1 and S1PR3 increased from first trimester towards term (P < 0.0001). S1PR1 was localized in endothelial cells, whereas S1PR2 and S1PR3 were predominantly found in villous trophoblasts. Furthermore, S1PR2 was found to be significantly down-regulated in BeWo cells when co-incubated with platelet-derived factors (P = 0.0055). CONCLUSION: This study suggests that the placental S1PR repertoire is differentially expressed across gestation. S1PR2 expression in villous trophoblasts is negatively influenced by platelet-derived factors, which could contribute to down-regulation of placental S1PR2 over time of gestation as platelet presence and activation in the intervillous space increases from the middle of the first trimester onwards.

Pancreatic Cancer and Platelets Crosstalk: A Potential Biomarker and Target.

Platelets have been recognized as key players in hemostasis, thrombosis, and cancer. Preclinical and clinical researches evidenced that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between cancer cells and platelets. Pancreatic cancer is a devastating disease with high morbidity and mortality worldwide. Although the relationship between pancreatic cancer and platelets in clinical diagnosis is described, the interplay between pancreatic cancer and platelets, the underlying pathological mechanism and pathways remain a matter of intensive study. This review summaries recent researches in connections between platelets and pancreatic cancer. The existing data showed different underlying mechanisms were involved in their complex crosstalk. Typically, pancreatic tumor accelerates platelet aggregation which forms thrombosis. Furthermore, extracellular vesicles released by platelets promote communication in a neoplastic microenvironment and illustrate how these interactions drive disease progression. We also discuss the advantages of novel model organoids in pancreatic cancer research. A more in-depth understanding of tumor and platelets crosstalk which is based on organoids and translational therapies may provide potential diagnostic and therapeutic strategies for pancreatic cancer progression.

Changes in Maternal Platelet Physiology during Gestation and Their Interaction with Trophoblasts.

Upon activation, maternal platelets provide a source of proinflammatory mediators in the intervillous space of the placenta. Therefore, platelet-derived factors may interfere with different trophoblast subtypes of the developing human placenta and might cause altered hormone secretion and placental dysfunction later on in pregnancy. Increased platelet activation, and the subsequent occurrence of placental fibrinoid deposition, are linked to placenta pathologies such as preeclampsia. The composition and release of platelet-derived factors change over gestation and provide a potential source of predicting biomarkers for the developing fetus and the mother. This review indicates possible mechanisms of platelet-trophoblast interactions and discusses the effect of increased platelet activation on placenta development.

Experimental supporting data on the influence of platelet-derived factors of malignant pleural effusions on T cell effector functions and their relevance in predicting prognosis of lung adenocarcinoma patients with pleural metastasis.

The data described in this article are supplementary to our primary article "Platelet factor 4 regulates T cell effector functions in malignant pleural effusions". Malignant pleural effusion (MPE) is a common complication of advanced lung adenocarcinoma (LAC) associated with a poor life expectancy [1]. Several challenges need to be addressed to identify non-invasive molecular biomarkers that help to predict the prognosis of LAC patients with MPE [2]. In the primary publication, we proposed that platelet-derived factors, especially platelet factor 4 (PF4), can negatively regulate T lymphocyte activation and granzyme B expression in pleural metastasis and its levels were associated with a worse prognosis. Here, we provide data on the influence of other platelet-derived factors, including transforming growth factor ß (TGF-ß), vascular endothelial factor (VEGF), and P-selectin on T lymphocyte response in MPE and their relevance as prognostic factors in lung cancer patients with pleural metastasis. Pleural fluids from 35 lung adenocarcinoma (LAC) and 20 heart failure (HF) patients were collected by thoracentesis and its platelet-derived factors' content was measured by specific enzyme-linked immunosorbent assay (ELISAs). Correlations between pleural levels of platelet-derived factors and T cell functions were analyzed by Pearson coefficients. Kaplan-Meier curves were used to estimate the effect of pleural concentrations of platelet-derived factors on overall survival of LAC patients with pleural metastasis. These analyses showed that the concentration of platelet-derived factors was not associated with T cell proliferation and cytotoxicity. Furthermore, their levels do not predict the survival of LAC with MPE.

Aplicación de las plaquetas con fines regenerativos en Cuba / Application of platelets with regenerative purposes in Cuba

Entre los pilares en que se apoya la Medicina Regenerativa están la terapia celular y la administración de factores bioactivos, fundamentalmente los derivados de las plaquetas. En los últimos años, la aplicación de plaquetas con fines regenerativos ha aportado nuevos conocimientos sobre sus posibilidades terapéuticas y se han obtenido avances prometedores con su empleo. En Cuba, el uso de plaquetas en la regeneración de tejidos se está aplicando con resultados favorables en un grupo significativo de enfermedades o condiciones clínicas y endiferentes especialidades, entre las que se encuentran ortopedia y traumatología, angiología, oftalmología, medicina del deporte.Los resultados obtenidos evidencian los beneficios que este tratamiento puede aportar a partir de un proceder simple, seguro, eficiente y económico(AU)

Among the pillars on which Regenerative Medicine is supported are cell therapy and the administration of bioactive factors, mainly those derived from platelets. In recent years, the application of platelets for regenerative purposes has brought new insights into their therapeutic possibilities and promising advances have been made with their use. In Cuba, the use of platelets in tissue regeneration is being applied with favorable results in a significant group of diseases or clinical conditions and different specialties, among which are orthopedics and traumatology, angiology, ophthalmology, sports medicine. The evidences show the benefits that this treatment can provide, from a simple, safe, efficient and economic procedure(AU)

Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment.

BACKGROUND: Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS. METHODS AND RESULTS: We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2α (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384). CONCLUSIONS: Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS.