1,720,976 research outputs found
Role of microvesicles in acute kidney injury.
No full textThe main function of microvesicles (MVs) is signaling through specific interactions with target cells and transferring gene products. Therefore, they may participate in physiological and pathological processes. Gaining further insights into the molecular specificity of MVs has allowed identifying the cellular source and may provide new diagnostic tools in the future. Indeed, an increasing body of evidence indicates that MVs may offer prognostic information in various diseases such as chronic inflammation, cardiovascular and renal diseases, pathological pregnancy, tumors, and sepsis. The presence of MVs in body fluids makes them readily accessible. Their number, cellular origin, composition and function can be dependent on the state of the disease. In sepsis for example, activated endothelial cells may shed MVs that might trigger leukocyte and monocyte production and release pro-oxidant and inflammatory mediators. MVs from platelets may trigger disseminated intravascular coagulopathy. MVs are no doubt also involved in modulating immunity and future studies will clarify their functional role in negatively modulating the cell response. In addition, the recognition of the signals delivered by MVs may open new therapeutic strategies. The removal of harmful MVs from plasma may be beneficial in pathological conditions where MVs deliver thrombogenic and inflammatory signals. On the other hand, MVs derived from stem cells may reprogram altered functions in target cells suggesting that they could be exploited in regenerative medicine to repair damaged tissues. We will discuss the role of stem cell-derived MVs in the repair of acute kidney injury
Exosomes/microvesicles as a mechanism of cell-to-cell communication.
No full textMicrovesicles (MVs) are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes of most cell types. An increasing body of evidence indicates that they play a pivotal role in cell-to-cell communication. Indeed, they may directly stimulate target cells by receptor-mediated interactions or may transfer from the cell of origin to various bioactive molecules including membrane receptors, proteins, mRNAs, microRNAs, and organelles. In this review we discuss the pleiotropic biologic effects of MVs that are relevant for communication among cells in physiological and pathological conditions. In particular, we discuss their potential involvement in inflammation, renal disease, and tumor progression, and the evidence supporting a bidirectional exchange of genetic information between stem and injured cells. The transfer of gene products from injured cells may explain stem cell functional and phenotypic changes without the need of transdifferentiation into tissue cells. On the other hand, transfer of gene products from stem cells may reprogram injured cells to repair damaged tissues
Role of L-selectin in the vascular homing of peripheral blood-derived endothelial progenitor cells
No full textEx vivo expanded endothelial progenitor cells (EPCs) represent a new potential approach for the revascularization of ischemic sites. However, local accumulation of infused EPCs in these sites is poor, and the mechanisms responsible for their homing are largely unknown. We observed the expression of L-selectin, an adhesion receptor that regulates lymphocyte homing and leukocyte rolling and migration, on ex vivo expanded blood-derived human EPCs. When EPCs were subcloned in SV40-T large Ag-transfected isolates, the copresence of L-selectin and endothelial lineage markers was confirmed. We therefore demonstrated that the expression of L-selectin by EPCs was functional because it mediates interaction with a murine endothelial cell line (H.end) expressing L-selectin ligands by way of transfection with alpha(1,3/4)-fucosyltransferase. Indeed, adhesion of EPCs after incubation at 4 degrees C on a rotating platform was enhanced on alpha(1,3/4)-fucosyltransferase-transfected H.end cells compared with control vector-transfected cells, and treatment with anti-L-selectin Abs prevented this event. We then studied the role of L-selectin in EPC homing in vivo. H.end cells were implanted s.c. in SCID mice to form endothelioma tumors, and EPCs were subsequently i.v. injected. L-selectin+ EPCs localized into alpha(1,3/4)-fucosyltransferase-transfected endothelial tumors to a greater extent than in control tumors, and they were able to directly contribute to tumor vascularization by forming L-selectin+ EPC-containing vessels. In conclusion, our results showed that a mechanism typical of leukocyte adhesion is involved in the vascular homing of EPCs within sites of selectin ligand expression. This observation may provide knowledge about the substrate to design strategies to improve EPC localization in damaged tissues
PAX2 expression by HHV-8–infected endothelial cells induced a proangiogenic and proinvasive phenotype
No full textHuman Herpesvirus 8 (HHV8), is considered the primary etiologic agent of Kaposi’s sarcoma (KS) as HHV8 infected endothelial cells acquire a KS-like phenotype.
In the present study we evaluated whether the infection of microvascular endothelial cells (HMEC) with HHV8 can trigger the expression of PAX2 oncogene and whether Pax2 protein is involved in HHV8-induced transformation of HMEC. We found that HHV8 infection induced the expression of both the PAX2 gene and Pax2 protein in HMEC but failed to induce Pax2 protein in HMEC stably transfected with PAX2 antisense (HMEC-AS). HHV8-infected HMEC but not HMEC-AS acquired proinvasive and proadhesive properties and enhanced survival and in vitro angiogenesis suggesting a correlation between Pax2 expression and the effects triggered by HHV8 infection. When HMEC expressing Pax2 by stably transfection with PAX2 sense gene or by HHV8 infection were implanted in vivo in SCID mice, enhanced angiogenesis and proliferative lesions resembling KS were observed. HHV8 infected HMEC-AS failed to induce angiogenesis and KS-like lesions. These results suggest that the expression of Pax2 is required for the proangiogenic and proinvasive changes induced by HHV8 infection in HMEC. In conclusion, HHV8 infection may activate an embryonic angiogenic program in HMEC by inducing the expression of PAX2 oncogene
Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury.
No full textBACKGROUND: Several studies demonstrated that mesenchymal stem cells (MSCs) reverse acute kidney injury (AKI) by a paracrine mechanism rather than by MSC transdifferentiation. We recently demonstrated that microvesicles (MVs) released from MSCs may account for this paracrine mechanism by a horizontal transfer of messenger RNA and microRNA.
METHODS: MVs isolated from MSCs were injected intravenously in rats (30 μg/rat) immediately after monolateral nephrectomy and renal artery and vein occlusion for 45 min. To evaluate the MV effects on AKI induced by ischaemia-reperfusion injury (IRI), the animals were divided into different groups: normal rats (n = 4), sham-operated rats (n = 6), IRI rats (n = 6), IRI + MV rats (n = 6), and IRI + RNase-MV rats (n = 6), and all animals were sacrificed at Day 2 after the operation. To evaluate the chronic kidney damage consequent to IRI, the rats were divided into different groups: sham-operated rats (n = 6) and IRI rats (n = 6), IRI + MV rats (n = 6), and all animal were sacrificed 6 months after the operation.
RESULTS: We found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation. The MVs also significantly reduced the impairment of renal function. Pretreatment of MVs with RNase to inactivate their RNA cargo abrogated these protective effects. Moreover, MVs by reducing the acute injury also protected from later chronic kidney disease.
CONCLUSION: MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach
Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA
No full textMembrane-derived microvesicles (MVs) are released from the cell surface and are implicated in cell-to-cell communication. We evaluated whether MVs derived from endothelial progenitor cells (EPCs) are able to trigger angiogenesis. We found that EPC-derived MVs were incorporated in endothelial cells by interaction with alpha4 and beta1 integrins expressed on the MV surface. In vitro, MVs promoted endothelial cell survival, proliferation, and organization in capillary-like structures. In vivo, in severe combined immunodeficient (SCID) mice, MV-stimulated human endothelial cells organized in patent vessels. When incubated with RNase, despite their internalization into endothelial cells, MVs failed to induce in vitro and in vivo angiogenic effects. mRNA transfer was shown by transduction of GFP protein in endothelial cells by MVs containing GFP-mRNA and the biologic relevance by the angiogenic effect of MV-mRNA extract delivered by lipofectamine. Microarray ana-lysis and quantitative reverse transcription-polymerase chain reaction (RT-PCR) of MV-mRNA extract indicated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated with the PI3K/AKT signaling pathway. Protein expression and functional studies showed that PI3K and eNOS play a critical role in the angiogenic effect of MVs. These results suggest that EPCs may activate angiogenesis in endothelial cells by releasing MVs able to trigger an angiogenic progra
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy
No full textOBJECTIVE: To determine whether HIV-1 Tat may directly alter glomerular permeability in HIV-associated nephropathy (HIVAN). DESIGN: Heavy proteinuria is a hallmark of HIVAN. The slit diaphragm is the ultimate glomerular filtration barrier critical for maintaining the efficiency of the ultrafiltration unit of the kidney. In this study, we evaluated the direct effect of Tat protein on the permeability of isolated glomeruli and on the expression of nephrin, the main slit diaphragm component, by human cultured podocytes. METHODS: Permeability was studied by measuring the permeability to albumin in isolated rat glomeruli. We also evaluated the expression of nephrin in human cultured podocytes by using immunofluorescence and Western blot. RESULTS: We found that Tat increased albumin permeability in isolated glomeruli, and rapidly induced the redistribution and loss of nephrin in cultured podocytes. Pretreatment of glomeruli and podocytes with blocking antibodies showed that Tat reduced nephrin expression by engaging vascular endothelial growth factor receptors types 2 and 3 and the integrin alphavbeta3. Pre-incubation of podocytes with two platelet-activating factor (PAF) receptor antagonists prevented the loss and redistribution of nephrin induced by Tat, suggesting that PAF is an intracellular mediator of Tat action. Tat induced a rapid PAF synthesis by podocytes. When podocytes transfected to overexpress PAF-acetylhydrolase, the main catabolic enzyme of PAF, were stimulated with Tat, the redistribution and loss of nephrin was abrogated. CONCLUSION: The present results define a mechanism by which Tat may reduce nephrin expression in podocytes, thus increasing glomerular permeability. This provides new insights in the understanding of HIVAN pathogenesis
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