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Find video protocols related to scientific articles indexed in Pubmed.
High-volume online haemodiafiltration improves erythropoiesis-stimulating agents (ESA) resistance in comparison with low-flux bicarbonate dialysis: results of the REDERT study.
Nephrol. Dial. Transplant.
PUBLISHED: 11-12-2014
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In haemodialysis (HD) patients, anaemia is associated with reduced survival. Despite treatment with erythropoiesis-stimulating agents (ESAs), a large number of patients with chronic kidney disease show resistance to this therapy and require much higher than usual doses of ESAs in order to maintain the recommended haemoglobin (Hb) target, and recent studies suggest that hepcidin (HEP) may mediate the ESA resistance index (ERI). High-volume online haemodiafiltration (HV-OL-HDF) has been shown to improve anaemia and to reduce the need for ESAs in HD patients; this effect is associated with a reduced inflammatory state in these patients. The aim of the REDERT study (role of haemodiafiltration on ERI) was to investigate the effect of different dialysis techniques on ERI and HEP levels in chronic dialysis patients.
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The case for treating refractory congestive heart failure with ultrafiltration.
Blood Purif.
PUBLISHED: 07-31-2014
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Extracellular fluid retention and congestion is a fundamental manifestation of heart failure (HF) and cardiorenal syndrome (CRS). Patients are normally hospitalized and treated with diuretics, but their outcomes are often poor as severe congestion and diuretics resistance is the primary cause of HF-related hospital admissions and readmissions. Isolated ultrafiltration (UF), which can be considered as a 'mechanical diuretic and natriuretic' tool, offers promise in achieving safe and effective fluid volume removal in HF patients with CRS who are resistant to stepwise guided diuretic therapy. This paper outlines the rationale for machine-driven isolated UF in CRS and the available clinical evidence regarding its use in patients with HF. In addition, this article summarizes some future clinical perspectives for expanding the use of UF therapy in HF patients in order to improve outcomes.
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Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury.
Stem Cells Dev.
PUBLISHED: 05-20-2014
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The mechanisms involved in renal repair by mesenchymal stromal cells (MSCs) are not entirely elucidated. The paracrine secretion of bioactive molecules has been implicated in the protective effects. Besides soluble mediators, MSCs have been shown to release extracellular vesicles (EVs), involved in renal repair process for different injury models. EVs have been shown to mediate communication between cells through the transference of several molecules, like protein, bioactive lipids, mRNA, and microRNAs (miRNAs). The miRNAs are noncoding RNAs that posttranscriptionally modulate gene expression and are involved in the regulation of several cellular processes, including those related to repair. The aim of the present study was to investigate the role of MSC-EVs in the modulation of miRNAs inside renal proximal tubular epithelial cells (PTECs) in an in vitro model of ischemia-reperfusion injury induced by ATP depletion. In this model we evaluated whether changes in miRNA expression were dependent on direct miRNA transfer or on transcription induction by MSC-EVs. The obtained results showed an enhanced incorporation of MSC-EVs in injured PTECs with protection from cell death. This biological effect was associated with EV-mediated miRNA transfer and with transcriptional modulation of miRNAs expressed by injured PTECs. Prediction of miRNA targets showed that miRNAs modulated in PTECs are involved in process of renal recovery with downregulation of coding-mRNAs associated with apoptosis, cytoskeleton reorganization, and hypoxia, such as CASP3 and 7, SHC1 and SMAD4. In conclusion, these results indicate that MSC-EVs may transfer and modulate the expression of several miRNAs involved in the repair and recovery process in PTECs.
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Human liver stem cells and derived extracellular vesicles improve recovery in a murine model of acute kidney injury.
Stem Cell Res Ther
PUBLISHED: 05-12-2014
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Several cellular sources of stem cells have been tested in the attempt to yield innovative interventions in acute kidney injury (AKI). Human liver stem cells (HLSCs) are cells isolated from the normal adult human liver which are gaining attention for their therapeutic potential. In the present study, we investigated whether HLSCs and the derived extracellular vesicles may promote tubular regeneration after AKI induced by glycerol injection in severe-combined immune-deficient mice.
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Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential.
Cell Commun. Signal
PUBLISHED: 04-04-2014
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Several studies demonstrate the role of adipose mesenchymal stem cells (ASCs) in angiogenesis. The angiogenic mechanism has been ascribed to paracrine factors since these cells secrete a plenty of signal molecules and growth factors. Recently it has been suggested that besides soluble factors, extracellular vesicles (EVs) that include exosomes and microvesicles may play a major role in cell-to-cell communication. It has been shown that EVs are implicated in the angiogenic process.
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Effects of fluid overload on heart rate variability in chronic kidney disease patients on hemodialysis.
BMC Nephrol
PUBLISHED: 01-30-2014
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While fluid overload (FO) and alterations in the autonomic nervous system (ANS) such as hypersympathetic activity, are known risk factors for cardiovascular morbidity and mortality in patients on chronic hemodialysis (HD), their relationship has not been thoroughly studied.
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Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes.
Diabetologia
PUBLISHED: 01-29-2014
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Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes.
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Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging.
Int. J. Mol. Med.
PUBLISHED: 01-17-2014
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Mesenchymal stem cells (MSCs) contribute to the recovery of tissue injury, providing a paracrine support. Cell-derived extracellular vesicles (EVs), carrying membrane and cytoplasmatic constituents of the cell of origin, have been described as a fundamental mechanism of intercellular communication. We previously demonstrated that EVs derived from human MSCs accelerated recovery following acute kidney injury (AKI) in vivo. The aim of the present study was to investigate the biodistribution and the renal localization of EVs in AKI. For this purpose, two methods for EV labeling suitable for in vivo tracking with optical imaging (OI), were employed using near infrared (NIR) dye (DiD): i) labeled EVs were generated by MSCs pre-incubated with NIR dye and collected from cell supernatants; ii) purified EVs were directly labeled with NIR dye. EVs obtained with these two procedures were injected intravenously (i.v.) into mice with glycerol-induced AKI and into healthy mice to compare the efficacy of the two labeling methods for in vivo detection of EVs at the site of damage. We found that the labeled EVs accumulated specifically in the kidneys of the mice with AKI compared with the healthy controls. After 5 h, the EVs were detectable in whole body images and in dissected kidneys by OI with both types of labeling procedures. The directly labeled EVs showed a higher and brighter fluorescence compared with the labeled EVs produced by cells. The signal generated by the directly labeled EVs was maintained in time, but provided a higher background than that of the labeled EVs produced by cells. The comparison of the two methods indicated that the latter displayed a greater specificity for the injured kidney.
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Isolation, characterization and potential role in beta cell-endothelium cross-talk of extracellular vesicles released from human pancreatic islets.
PLoS ONE
PUBLISHED: 01-01-2014
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The cross-talk between beta cells and endothelium plays a key role in islet physiopathology and in the revascularization process after islet transplantation. However, the molecular mechanisms involved in this cross-talk are not fully elucidated. Extracellular vesicles (EVs) are secreted membrane nanoparticles involved in inter-cellular communication through the transfer of proteins and nucleic acids. The aims of this study were: 1) isolation and characterization of EVs from human islets; 2) evaluation of the pro-angiogenic effect of islet-derived EVs on human islet endothelial cells (IECs). EVs were isolated by ultracentrifugation from conditioned medium of human islets and characterized by nanotrack analysis (Nanosight), FACS, western blot, bioanalyzer, mRNA/microRNA RT-PCR array. On IECs, we evaluated EV-induced insulin mRNA transfer, proliferation, resistance to apoptosis, in vitro angiogenesis, migration, gene and protein profiling. EVs sized 236±54 nm, expressed different surface molecules and islet-specific proteins (insulin, C-peptide, GLP1R) and carried several mRNAs (VEGFa, eNOS) and microRNAs (miR-27b, miR-126, miR-130 and miR-296) involved in beta cell function, insulin secretion and angiogenesis. Purified EVs were internalized into IECs inducing insulin mRNA expression, protection from apoptosis and enhancement of angiogenesis. Human islets release biologically active EVs able to shuttle specific mRNAs and microRNAs (miRNAs) into target endothelial cells. These results suggest a putative role for islet-derived EVs in beta cell-endothelium cross-talk and in the neoangiogenesis process which is critical for engraftment of transplanted islets.
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Dissecting paracrine effectors for mesenchymal stem cells.
Adv. Biochem. Eng. Biotechnol.
PUBLISHED: 06-26-2013
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There has been increasing interest in the application of mesenchymal stem cells (MSCs) in regenerative medicine in recent years. In this context, the beneficial effects of MSCs have been ascribed mainly to a paracrine action rather than to direct replacement of the injured tissue. Indeed, MSCs produce a great variety of trophic and immunomodulatory factors. In this chapter, we provide an overview of growth factors and chemokines involved in stimulation of cell proliferation, inhibition of apoptosis, enhancement of angiogenesis, and suppression of inflammatory and immune response. In addition, we discuss the emerging role of the extracellular vesicles released from MSCs as possible paracrine mediators.
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Patricio Godoy, Nicola J Hewitt, Ute Albrecht, Melvin E Andersen, Nariman Ansari, Sudin Bhattacharya, Johannes Georg Bode, Jennifer Bolleyn, Christoph Borner, Jan Böttger, Albert Braeuning, Robert A Budinsky, Britta Burkhardt, Neil R Cameron, Giovanni Camussi, Chong-Su Cho, Yun-Jaie Choi, J Craig Rowlands, Uta Dahmen, Georg Damm, Olaf Dirsch, María Teresa Donato, Jian Dong, Steven Dooley, Dirk Drasdo, Rowena Eakins, Karine Sá Ferreira, Valentina Fonsato, Joanna Fraczek, Rolf Gebhardt, Andrew Gibson, Matthias Glanemann, Chris E P Goldring, Maria José Gómez-Lechón, Geny M M Groothuis, Lena Gustavsson, Christelle Guyot, David Hallifax, Seddik Hammad, Adam Hayward, Dieter Häussinger, Claus Hellerbrand, Philip Hewitt, Stefan Hoehme, Hermann-Georg Holzhütter, J Brian Houston, Jens Hrach, Kiyomi Ito, Hartmut Jaeschke, Verena Keitel, Jens M Kelm, B Kevin Park, Claus Kordes, Gerd A Kullak-Ublick, Edward L Lecluyse, Peng Lu, Jennifer Luebke-Wheeler, Anna Lutz, Daniel J Maltman, Madlen Matz-Soja, Patrick McMullen, Irmgard Merfort, Simon Messner, Christoph Meyer, Jessica Mwinyi, Dean J Naisbitt, Andreas K Nüssler, Peter Olinga, Francesco Pampaloni, Jingbo Pi, Linda Pluta, Stefan A Przyborski, Anup Ramachandran, Vera Rogiers, Cliff Rowe, Celine Schelcher, Kathrin Schmich, Michael Schwarz, Bijay Singh, Ernst H K Stelzer, Bruno Stieger, Regina Stöber, Yuichi Sugiyama, Ciro Tetta, Wolfgang E Thasler, Tamara Vanhaecke, Mathieu Vinken, Thomas S Weiss, Agata Widera, Courtney G Woods, Jinghai James Xu, Kathy M Yarborough, Jan G Hengstler.
Arch. Toxicol.
PUBLISHED: 05-02-2013
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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4?, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4?), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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Human liver stem cells improve liver injury in a model of fulminant liver failure.
Hepatology
PUBLISHED: 03-05-2013
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Liver transplantation is currently the only effective therapy for fulminant liver failure, but its use is limited by the scarcity of organs for transplantation, high costs, and lifelong immunosuppression. Here we investigated whether human liver stem cells (HLSCs) protect from death in a lethal model of fulminant liver failure induced by intraperitoneal injection of D-galactosamine and lipopolysaccharide in SCID mice. We show that injection of HLSCs and of HLSC-conditioned medium (CM) significantly attenuates mouse mortality in this model. Histopathological analysis of liver tissue showed reduction of liver apoptosis and enhancement of liver regeneration. By optical imaging we observed a preferential localization of labeled HLSCs within the liver. HLSCs were detected by immunohistochemistry in large liver vessels (at 24 hours) and in the liver parenchyma (after day 3). Fluorescence in situ hybridization analysis with the human pan-centromeric probe showed that positive cells were cytokeratin-negative at 24 hours. Coexpression of cytokeratin and human chromosome was observed at 7 and, to a lesser extent, at 21 days. HLSC-derived CM mimicked the effect of HLSCs in vivo. Composition analysis of the HLSC-CM revealed the presence of growth factors and cytokines with liver regenerative properties. In vitro experiments showed that HLSC-CM protected human hepatocytes from apoptosis and enhanced their proliferation.
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On-line hemodiafiltration in the large RISCAVID study.
Contrib Nephrol
PUBLISHED: 12-15-2011
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Despite significant advances in hemodialysis (HD) and medical therapy, mortality rates in patients with chronic kidney disease stage 5 (CKD-5D) remain unacceptably high, with cardiovascular (CV) mortality risk in dialysis patients being several times higher than that of a general population. The CV mortality risk of a 25-to 34-year-old dialysis patient is approximately the same as the one of an otherwise healthy person aged over 85 in the general population. HD patients are not only exposed to the various traditional risk factors valid for the general population but in addition also to the non-traditional risk factors resulting either from uremia per se or from the dialysis treatment. Our understanding of chronic inflammation in CKD-5D and of its influence in the accelerated atherosclerotic process has greatly evolved. Dialysis therapy, performed efficiently, has the potential to provide CKD-5D patients with benefits beyond the life-saving function of removal accumulated waste products and excess fluid. There is sufficient evidence to indicate that on-line hemodiafiltration has the potential to improve chronic inflammation, fluid overload, left ventricular hypertrophy, anemia and quality of life of CKD-5D patients. In the search for more effective, safer and less expensive approaches to the management of the above conditions, an innovative concept of biocompatibility should be broadened to the HD system/patient evaluation. Here, we intend to present new insights obtained from a prospective observational study (RISCAVID, RISchio CArdiovascolare nei pazienti afferenti allArea Vasta In Dialisi) performed on a large HD population in the northwestern region of Tuscany, Italy, on the assessment of the different parameters of chronic inflammation and gross/CV mortality and anemia management.
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MicroRNAs and mesenchymal stem cells.
Vitam. Horm.
PUBLISHED: 12-01-2011
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In the adult body, mesenchymal stem cells (MSCs) represent a population with self-renewal ability and multipotent differentiation capabilities. The phenotype of these cells is modulated by a dynamic interplay of signals within a defined microenvironment. Recent studies indicate that microRNAs (miRNAs) act as regulatory signals for maintaining of stemless, self-renewal, and differentiation in embryonic and adult stem cells. miRNAs are noncoding RNAs with pleiotropic effect dependent on posttranscriptional regulation of gene expression. In the stem cell biology, miRNAs by repressing translation of specific mRNAs, may determine the fate of these cells. The characterization of miRNAs present in MSCs may be relevant not only as signature of the cell type but also for the understanding of their biological activities. Recent studies indicate also that the exchange of miRNAs between neighboring cells is an integral part of MSC communication with tissue-injured cells. The transport of miRNAs within biological fluids is guaranteed by microvesicles (MVs) that after release from the cell of origin may enter into a target cell delivering their cargo. MVs may allow a bidirectional exchange of miRNAs between injured cells and MSCs. The exchange of genetic information may on one hand, reprogram the phenotype of MSCs, to acquire features of the injured tissues. On the other hand, MVs derived from stem cells may activate regenerative programs in cells survived to injury. The study of miRNAs, their biological function, and their transfer opens a new dimension on the fate and behavior of MSCs and on their potential application in regenerative medicine.
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Role of microvesicles in acute kidney injury.
Contrib Nephrol
PUBLISHED: 09-09-2011
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The 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.
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Alteration of autonomic blood pressure control during hemodialysis in peripheral vascular disease patients.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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Blood pressure (BP) response to volume depletion induced by hemodialysis (HD) treatment may be important to understand the pathophysiology of the increased mortality in HD patients with vascular calcification. In the present study a comparison between end stage renal disease (ESRD) patients affected by peripheral vascular disease (PVD) and ESRD patients without PVD was performed. Continuous blood pressure was recorded at the beginning and at the end of HD. BP and heart rate variability (HRV) were analyzed to quantify the autonomic nervous system regulation of heart beat and peripheral resistance. PVD patients showed an increase of pulse pressure (PP) during HD, an altered autonomic peripheral control, a lower sympathetic activity, with respect to ESRD patients without PVD.
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Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche.
Cancer Res.
PUBLISHED: 06-13-2011
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Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression.
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The rise of hemodialysis machines: new technologies in minimizing cardiovascular complications.
Expert Rev Cardiovasc Ther
PUBLISHED: 04-02-2011
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Hemodialysis (HD) is a life-saving treatment for more than 1,700,000 patients with chronic kidney disease (CKD) stage V. Every year the HD population becomes increasingly older (average age: 75 years) and more ill due to the associated comorbidities such as cardiovascular disease (heart failure, coronary heart disease and peripheral vascular disease), diabetes, hypertension and peripheral vascular disease. Most of the complications associated with HD involve the cardiovascular system. HD machines have been greatly improved over the last 30 years. We have moved from HD machines simply allowing extracorporeal circulation to high technological medical devices capable of very precisely controlling ultrafiltration, dialysis dose, the patients core temperature, circulating plasma volume, plasma sodium and producing unlimited volumes of ultrapure dialysate. In this article, we will focus on some of the fundamental achievements in HD machine technology, with particular reference to monitoring tools and bioengineering approaches for biosignal analysis. We propose that along these lines of further development, HD machines in the future will enable a better online identification of patients at higher cardiovascular risk, thus allowing clinicians to select more appropriate treatment modalities and parameters.
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The role of microvesicles in tissue repair.
Organogenesis
PUBLISHED: 04-01-2011
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Microvesicles (MVs) are released by almost all cells in resting and activated conditions. First described several years ago, it is only recently that their mechanisms of action are being elucidated, and their potential role in health and disease is drawing increasing attention. The main function of MVs is signaling through specific interactions with target cells and the transferring of gene products. Gaining further insights into the molecular specificity of MVs has allowed identification of the cellular source and may provide new diagnostic tools in the future. Indeed, an increasing body of evidence indicates that MVs are capable of mediating tissue repair in models of acute kidney and liver injury. In this review, we will discuss the mechanisms through which MVs from stem cells may act on target cells and may modify the response to injury. Furthermore, MVs from inflammatory cells are suspected to be involved in various diseases, such as cardiovascular and renal diseases, pathological pregnancy, tumors and sepsis. MVs are no doubt also involved in modulating immunity, and future studies will clarify their functional role in negatively modulating the cell response. Their role in physiological and pathological processes is increasingly appreciated. Depending on the cell source and the condition, MVs may be either beneficial or detrimental to the host. The recognition of their pathogenetic role may suggest new approaches to future therapies.
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Blood and ultrafiltrate dosage of citrate as a useful and routine tool during continuous venovenous haemodiafiltration in septic shock patients.
Nephrol. Dial. Transplant.
PUBLISHED: 03-08-2011
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Citrate anticoagulation is gaining popularity in renal replacement therapies (RRT) for critically ill patients. In order to study whether citrate accumulates in septic shock patients, we determined citrate in plasma and dialysate during continuous venovenous haemodiafiltration (CVVHDF).
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Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study.
Nephrol. Dial. Transplant.
PUBLISHED: 02-16-2011
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Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality.
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Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury.
Nephrol. Dial. Transplant.
PUBLISHED: 02-15-2011
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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.
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Study of the autonomic response in hemodialysis patients with different fluid overload levels.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 11-25-2010
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This work aims at studying the autonomic nervous system (ANS) response to hemodialysis (HD) treatment in a population of end stage renal disease (ESRD) patients. ECG Holter recordings and whole body bioimpedance spectroscopy measurements were performed for each patient. Patients were classified according to the fluid overload (FO) values and the systolic blood pressure (SBP) measured before HD. Time domain and frequency domain indices from heart rate variability (HRV) signals were measured for the first 30 minutes and last 30 minutes of HD, the first hour after HD, and night (12.00 p.m.-4 a.m.). Significant differences were obtained in fluid overloaded but normotensive patients (Group IV) with respect to fluid overloaded and hypertensive patients (Group I) and normohydrated and normotensive patients (Group N+Dx). In particular, SDNN, RMSSD, SDSD, pNN50%, indices resulted significantly higher in Group IV with respect to the other groups. Overhydrated patients with hypertension (Group I) showed a blunted parasympathetic activity, which is supposed to contribute to hypertension.
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Relative blood volume monitoring during hemodialysis in end stage renal disease patients.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 11-25-2010
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A crucial point in the haemodialysis (HD) treatment is the reliable assessment of hydration status. An inadequate removed volume may lead to chronic fluid overload which can lead to hypertension, left ventricular hypertrophy and heart failure. Therefore, the estimation of the hydration state and the management of a well-tolerated water removal is an important challenge. This exploratory study aims at identifying new parameters obtained from continuous Blood Volume Monitoring (BVM) allowing a qualitative evaluation of hydration status for verifying the adequacy of HD setting parameters (e.g UFR, target dry weight). The percentage of blood volume reduction (BVR%) during HD was compared against a gold standard method for hydration status assessment. The slope of the first 30 minute of blood volume reduction (BVR) was proposed as a useful parameter to identify overhydrated patients.
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Exosome/microvesicle-mediated epigenetic reprogramming of cells.
Am J Cancer Res
PUBLISHED: 10-19-2010
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Microvesicles (MVs) are released by different cell types and may remain in the extracellular space in proximity of the cell of origin or may enter the biological fluids. MVs released by tumor cells are detectable in patients with cancer and their number in the circulation correlates with poor prognosis. Recent studies demonstrated that MVs may act as mediator of cell-to-cell communication thus ensuring short- and long-range exchange of information. Due to their pleyotropic effects, MVs may play a role in the prothrombotic state associated with cancer as well as in cancer development and progression. It has been recently shown that MVs may induce epigenetic changes in target cells by transferring genetic information. This finding suggests that tumor and stromal cells may talk each other via MVs to establish a favorable tumor niche and to promote tumor growth, invasiveness and progression. Moreover, MVs contain genetic material under the form of mRNA and microRNA, that may allow an easy screening for cancer genetic markers and offer new diagnostic and prognostic information. This review presents an overview of the many biological actions of MVs and of the potential role of MV-mediated exchange of genetic information among cells in tumor biology.
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Darbepoetin-? treatment enhances glomerular regenerative process in the Thy-1 glomerulonephritis model.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 09-08-2010
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Recent studies have demonstrated that erythropoietin (EPO) and its analogs induce cytoprotective effects on many nonerythroid cells. In this study, we examined whether darbepoetin-? might prevent glomerular lesions in the Thy-1.1 model of glomerulonephritis (Thy-1-GN). GN was induced in Wistar rats by a single injection of monoclonal anti-Thy-1.1 antibody. Rats were killed at 24 h, 72 h, 7 days, 10 days, or 15 days after antibody injection. Kidneys were removed for histological analysis, and proteinuria was measured. Because at day 7 the maximal degree of renal damage and proteinuria was found, the effect of darbepoetin-? was tested at day 7 and two different protocols of administration were used; After anti-Thy-1.1 injection, rats received two doses of darbepoetin-? or vehicle at days 0 and 4 or at days 4 and 6. At day 7, proteinuria, plasma creatinine concentration, and renal morphology analysis were performed. Also, ?-actin, desmin, caspase-3, and Ki67 protein expression were evaluated by immunohistochemistry. Our results showed that in both protocols of administration, darbepoetin-? treatment decreased proteinuria in Thy-1-GN rats and this effect correlated with the improvement in renal morphology. Glomerular lesions, ?-actin, and caspase-3 protein expression, observed in most glomeruli of Thy-1-GN rats, were significantly reduced in darbepoetin-?-treated rats, while cell proliferation was significantly enhanced. The results indicate that darbepoetin-? treatment promotes glomerular recovery.
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A combining method to enhance the in vitro differentiation of hepatic precursor cells.
Tissue Eng Part C Methods
PUBLISHED: 07-10-2010
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The ideal bioartificial liver should be designed to reproduce as nearly as possible in vitro the habitat that hepatic cells find in vivo. In the present work, we investigated the in vitro perfusion condition with a view to improving the hepatic differentiation of pluripotent human liver stem cells (HLSCs) from adult liver. Tissue engineering strategies based on the cocultivation of HLSCs with hepatic stellate cells (ITO) and with several combinations of medium were applied to improve viability and differentiation. A mathematical model estimated the best flow rate for perfused cultures lasting up to 7 days. Morphological and functional assays were performed. Morphological analyses confirmed that a flow of perfusion medium (assured by the bioreactor system) enabled the in vitro organization of the cells into liver clusters even in the deeper levels of the sponge. Our results showed that, when cocultured with ITO using stem cell medium, HLSCs synthesized a large amount of albumin and the MTT test confirmed an improvement in cell proliferation. In conclusion, this study shows that our in vitro cell conditions promote the formation of clusters of HLSCs and enhance the functional differentiation into a mature hepatic population.
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Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs.
PLoS ONE
PUBLISHED: 02-17-2010
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Cell-derived microvesicles (MVs) have been described as a new mechanism of cell-to-cell communication. MVs after internalization within target cells may deliver genetic information. Human bone marrow derived mesenchymal stem cells (MSCs) and liver resident stem cells (HLSCs) were shown to release MVs shuttling functional mRNAs. The aim of the present study was to evaluate whether MVs derived from MSCs and HLSCs contained selected micro-RNAs (miRNAs).
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Dialysis prescription: A modifiable risk factor for chronic kidney disease patients.
Blood Purif.
PUBLISHED: 01-26-2010
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Recent surveys of hemodialysis studies strongly support the fact that dialysis prescription is a modifiable risk factor. Six tracks to improve dialysis patient outcomes have been identified: change in vascular access option strategy and restricting catheter use; increasing time or frequency of dialysis sessions; assessment and management of fluid status; favoring removal of middle and large molecules by high-flux and convective clearance; considering ultrapurity of dialysis fluid purity as a new standard and a part of hemodialysis biocompatibility, and improving quality care and patient follow-up. By modifying dialysis prescription and by implementing a continuous quality assurance program it appears possible to improve dialysis patient survival.
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Protective effect of resin adsorption on septic plasma-induced tubular injury.
Crit Care
PUBLISHED: 01-11-2010
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A pro-apoptotic effect of circulating mediators on renal tubular epithelial cells has been involved in the pathogenesis of sepsis-associated acute kidney injury (AKI). Adsorption techniques have been showed to efficiently remove inflammatory cytokines from plasma. The aim of this study was to evaluate the efficiency of the hydrophobic resin Amberchrom CG161 M to adsorb from septic plasma soluble mediators involved in tubular injury.
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The dynamic stem cell microenvironment is orchestrated by microvesicle-mediated transfer of genetic information.
Histol. Histopathol.
PUBLISHED: 01-08-2010
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It has been commonly supposed that adult stem cells co-localize with supporting cells within specific regions or specialized microenvironment in each tissue/organ, called stem cell niche. This concept was based on the assumption that stem cells are intrinsically hierarchical in nature. However, recent data indicate that stem cells may represent a continuum with reversible alterations in phenotype taking place during the transit through cell cycle. Based on this dynamic interpretation it has been suggested that the so-called niche is represented by a single or only few cell types continually adjusting their phenotype and function to individual circumstances. A critical component in the regulation of the continuum of stem cell phenotypes is the microenvironment. In this context, microvesicles (MVs) account for the transfer of genetic information between cells. Originally considered inert cellular debris, MVs are increasingly recognized to be important mediators of cell-to-cell communication. MVs may transfer receptors, proteins, mRNA and microRNA to target cells via specific receptor-mediated interaction. In stem cell biology the exchange of genetic information may be bidirectional from stromal to stem cells. In the context of tissue injury the MV-mediated transfer of genetic information may reprogram the phenotype of stem cells to acquire features of the injured tissue cells. In addition, MVs derived from stem cells may induce de-differentiation of cells which have survived injury with a cell cycle re-entry that may allow tissue regeneration. In the present review we discuss the possibility of a continuous genetic modulation of stem cells by a MV-mediated transfer of information between cells.
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Introduction of a novel prototype bioartificial liver support system utilizing small human hepatocytes in rotary culture.
Tissue Eng Part A
PUBLISHED: 07-18-2009
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The aim of this study was to establish a stand-alone, perfused, rotary cell culture system using small human hepatocytes (SH) for bioartificial liver (BAL) support. SH were grown on cytodex 3 microcarriers (beads) to a maximum density of 1.2 +/- 0.3 x 10(7) cells per mL within 12 days. Size of aggregates formed by up to 15 beads was regulated by rotation speed. Cell function was proven by treatment with ammonia and galactose, and metabolism was analyzed. Treatment strategy was comprised of two phases, namely growth phase and treatment phase. Cells were grown for 6 days and subsequently incubated with ammonia or galactose for 2 days, followed by a 2-day regeneration period and another 2-day treatment phase. Consumption of glucose, release of lactate dehydrogenase, formation of lactate, and production of urea and albumin were determined regularly. Mean galactose consumption was 50 microg per 106 cells per hour, ammonia-induced urea formation was 3.6 microg per 106 cells per hour, and albumin production was 110 ng per 106 cells per hour. All metabolic parameters followed a logarithmic trend and were found to be very stable in the second half of the culture period when cells were treated with ammonia or galactose. Dissolved oxygen (%DO), pH, and temperature were monitored in-stream at intervals of 7 min, and the values were logged. Viability and morphology of cells were monitored via confocal microscopy. Viability was around 95% in controls and 90% during treatment. Promising results were obtained in support of our ongoing efforts to establish a fully autonomous BAL support device utilizing SH as a bridge to transplantation.
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Isolation and characterization of resident mesenchymal stem cells in human glomeruli.
Stem Cells Dev.
PUBLISHED: 07-07-2009
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In humans, renal resident stem cells were identified within the interstitium, the tubular cells, and the Bowmans capsule. The aim of the present study was to investigate whether multipotent stem cells are present also in the adult human-decapsulated glomeruli and whether they represent a resident population. We found that human glomeruli deprived of the Bowmans capsule contain a population of CD133+CD146+ cells and a population of CD133-CD146+ cells expressing mesenchymal stem cell (MSC) markers and renal stem cell markers CD24 and Pax-2. The CD133+CD146+ cells differed from those previously isolated from Bowmans capsule as they co-expressed endothelial markers, such as CD31 and von Willebrand factor (vWF), were CD24-negative and were not clonogenic, suggesting an endothelial commitment. The glomerular mesenchymal CD133-CD146+ population (Gl-MSC) exhibited self-renewal capability, clonogenicity, and multipotency. In addition to osteogenic, adipogenic, and chondrogenic differentiation, these cells were able to differentiate to endothelial cells and epithelial cells expressing podocytes markers such as nephrin, podocin, and synaptopodin. Moreover, Gl-MSC when cultured in appropriate conditions, acquired mesangial cell markers such as alpha-smooth muscle actin (alpha-SMA) and angiotensin II (AT-II) receptor I. The expression of the embryonic organ-specific PAX-2 gene and protein and of donor sex identity when isolated from glomeruli of a renal allograft suggested these cells to be a tissue resident population. In conclusion, these results indicate the presence of a multipotent mesenchymal cell population resident in human glomeruli that may have a role in the physiological cell turnover and/or in response to glomerular injury.
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Carbamylated darbepoetin derivative prevents endothelial progenitor cell damage with no effect on angiogenesis.
J. Mol. Cell. Cardiol.
PUBLISHED: 04-27-2009
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Erythropoietin (EPO) prevents cell apoptosis induced by oxidative stress. Carbamylated EPO maintains the tissue-protective activities of the unmodified EPO but does not stimulate erythropoiesis. This study evaluates whether carbamylated erythropoietin is as effective as recombinant human erythropoietin in protecting endothelial progenitor cells (EPCs) from apoptosis without stimulating erythropoiesis. Experiments were performed in an erythroid cell line (UT-7) and in human EPCs. Cell signals regulating proliferation and apoptosis (Jak-2, Akt, Erk1/2, NFkappaB and Stat-5) were measured by Western blotting. In human EPCs, cell senescence, apoptosis and proliferation were assessed by acidic beta-gal and measurement of telomere length, TUNEL and PCNA labeling, respectively. Angiogenesis was evaluated using the endothelial tube formation assay. In UT-7, carbamylated erythropoietin (C-darbe) induced phosphorylation of the anti-apoptotic Jak-2/Akt signal and, as opposed to recombinant human erythropoietin (darbe), did not produce a significant activation of cell proliferating signals. Darbe increased the percent of proliferating EPCs and promoted angiogenesis. By contrast, C-darbe failed to stimulate proliferation of EPCs. Both C-darbe and darbe equally reduced apoptosis and senescence. Thus, C-darbe protects EPCs from apoptosis and does not increase erythropoiesis.
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Mesenchymal stem cell-derived microvesicles protect against acute tubular injury.
J. Am. Soc. Nephrol.
PUBLISHED: 04-23-2009
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Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.
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The role of microvesicles derived from mesenchymal stem cells in tissue regeneration; a dream for tendon repair?
Muscles Ligaments Tendons J
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Tendon injuries represent even today a challenge as repair may be exceedingly slow and incomplete. Regenerative medicine and stem cell technology have shown to be of great promise. Here, we will review the current knowledge on the mechanisms of the regenerative potential of mesenchymal stem cells (MSCs) obtained from different sources (bone marrow, fat, cord blood, placenta). More specifically, we will devote attention to the current use of MSCs that have been used experimentally and in limited numbers of clinical cases for the surgical treatment of subchondral-bone cysts, bone-fracture repair and cartilage repair. Based on the recently emerging role in regenerative mechanisms of soluble factors and of extracellular vesicles, we will discuss the potential of non-cellular therapies in horse tendon injuries.
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Extracellular vesicles as an emerging mechanism of cell-to-cell communication.
Endocrine
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The concept that extracellular vesicles may act as paracrine/endocrine effectors is based on the evidence that they are able to transport bioactive molecules between cells, either within a defined microenvironment or remotely, by entering the biologic fluids. Extracellular vesicles, including exosomes and microvesicles, may deliver lipids and various functional transcripts, released from the cell of origin, to target cells. Since extracellular vesicles contain defined patterns of mRNA, microRNA, long non-coding RNA, and occasionally genomic DNA, they may transfer genetic information which induces transient or persistent phenotypic changes in recipient cells. In this review, we will discuss potential physiologic and pathological implications of extracellular vesicles, as well as the diagnostic and therapeutic opportunities that they may provide.
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Epidemiological study of 7316 patients on haemodialysis treated in FME clinics in Spain, using data from the EuCliD® database: results from years 2009-2010.
Nefrologia
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Observational study of patients on hemodialysis (HD) in FMC® Spain clinics over the years 2009 and 2010. The data were collected from the EuClid® database, implemented in the clinics of FMC®, which complies with the following feature: record online, compulsory, conducted in patients incidents and that it covers the entire population on HD in these clinics. Its aim is to understand the characteristics of patients and treatment patterns, comparing them with other studies described in the literature and in order to improve their prognosis and quality of life. Include 2637 incidents patients and 4679 prevalent, which makes a total of 7316 patients. In prevalent patients: 24.4% were diabetic; 76.3% had cardio-vascular disease (CVD) and 13.4% cancer. Among the incidents, these percentages were: 33.5% diabetic; 80.6% had CVD and 12.6% cancer. The prevalent patients had such as vascular access: FAV 68.5%, prosthesis 5.6%, permanent catheter 23.7% and 2.3% temporary catheter. The average of the duration of the sessions of HD was 230 minutes. 23.2% of the prevalent patients were on on-line hemodiafiltration. These patients hospitalization rates were 0.46 hospitalizations per incident patient per year and 0.52 per prevalent patient per year. The annual gross mortality rate was 12%. The mortality of the patients in this study HD is smaller than these of the Spanish Registry of Dialysis and Transplant (GRER). The result of morbidity and mortality of the FMC clinics of Spain can, therefore, be as good compared with these of the GRER and other international series. That does not mean that there are not areas of improvement as the increase in the time of dialysis, the percentage of patients on on-line hemodiafiltration convective techniques and the percentage of FAV.
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Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth.
Stem Cells Dev.
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Mesenchymal stem cells (MSCs) have opposite effects on tumor growth, being able either to favor angiogenesis and tumor initiation or to inhibit progression of established tumors. Factors produced by MSCs within the tumor microenvironment may be relevant for their biological effects. Recent studies demonstrated that microvesicles (MVs) are an integral component of inter-cellular communication within the tumor microenvironment. In the present study, we evaluated whether MVs derived from human bone marrow MSCs may stimulate or inhibit in vitro and in vivo growth of HepG2 hepatoma, Kaposis sarcoma, and Skov-3 ovarian tumor cell lines. We found that MVs inhibited cell cycle progression in all cell lines and induced apoptosis in HepG2 and Kaposis cells and necrosis in Skov-3. The observed activation of negative regulators of cell cycle may explain these biological effects. In vivo intra-tumor administration of MVs in established tumors generated by subcutaneous injection of these cell lines in SCID mice significantly inhibited tumor growth. In conclusion, MVs from human MSCs inhibited in vitro cell growth and survival of different tumor cell lines and in vivo progression of established tumors.
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Therapeutic potential of mesenchymal stem cell-derived microvesicles.
Nephrol. Dial. Transplant.
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Several studies have demonstrated that mesenchymal stem cells have the capacity to reverse acute and chronic kidney injury in different experimental models by paracrine mechanisms. This paracrine action may be accounted for, at least in part, by microvesicles (MVs) released from mesenchymal stem cells, resulting in a horizontal transfer of mRNA, microRNA and proteins. MVs, released as exosomes from the endosomal compartment, or as shedding vesicles from the cell surface, are now recognized as being an integral component of the intercellular microenvironment. By acting as vehicles for information transfer, MVs play a pivotal role in cell-to-cell communication. This exchange of information between the injured cells and stem cells has the potential to be bi-directional. Thus, MVs may either transfer transcripts from injured cells to stem cells, resulting in reprogramming of their phenotype to acquire specific features of the tissue, or conversely, transcripts could be transferred from stem cells to injured cells, restraining tissue injury and inducing cell cycle re-entry of resident cells, leading to tissue self-repair. Upon administration with a therapeutic regimen, MVs mimic the effect of mesenchymal stem cells in various experimental models by inhibiting apoptosis and stimulating cell proliferation. In this review, we discuss whether MVs released from mesenchymal stem cells have the potential to be exploited in novel therapeutic approaches in regenerative medicine to repair damaged tissues, as an alternative to stem cell-based therapy.
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Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs.
Stem Cells
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Microvesicles (MVs) play a pivotal role in cell-to-cell communication. Recent studies demonstrated that MVs may transfer genetic information between cells. Here, we show that MVs derived from human adult liver stem cells (HLSC) may reprogram in vitro HepG2 hepatoma and primary hepatocellular carcinoma cells by inhibiting their growth and survival. In vivo intratumor administration of MVs induced regression of ectopic tumors developed in SCID mice. We suggest that the mechanism of action is related to the delivery of microRNAs (miRNAs) from HLSC-derived MVs (MV-HLSC) to tumor cells on the basis of the following evidence: (a) the rapid, CD29-mediated internalization of MV-HLSC in HepG2 and the inhibition of tumor cell growth after MV uptake; (b) the transfer by MV-HLSC of miRNAs with potential antitumor activity that was downregulated in HepG2 cells with respect to normal hepatocytes; (c) the abrogation of the MV-HLSC antitumor effect after MV pretreatment with RNase or generation of MVs depleted of miRNAs; (d) the relevance of selected miRNAs was proven by transfecting HepG2 with miRNA mimics. The antitumor effect of MV-HLSC was also observed in tumors other than liver such as lymphoblastoma and glioblastoma. These results suggest that the delivery of selected miRNAs by MVs derived from stem cells may inhibit tumor growth and stimulate apoptosis.
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Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells.
Kidney Int.
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Endothelial progenitor cells are known to reverse acute kidney injury by paracrine mechanisms. We previously found that microvesicles released from these progenitor cells activate an angiogenic program in endothelial cells by horizontal mRNA transfer. Here, we tested whether these microvesicles prevent acute kidney injury in a rat model of ischemia-reperfusion injury. The RNA content of microvesicles was enriched in microRNAs (miRNAs) that modulate proliferation, angiogenesis, and apoptosis. After intravenous injection following ischemia-reperfusion, the microvesicles were localized within peritubular capillaries and tubular cells. This conferred functional and morphologic protection from acute kidney injury by enhanced tubular cell proliferation, reduced apoptosis, and leukocyte infiltration. Microvesicles also protected against progression of chronic kidney damage by inhibiting capillary rarefaction, glomerulosclerosis, and tubulointerstitial fibrosis. The renoprotective effect of microvesicles was lost after treatment with RNase, nonspecific miRNA depletion of microvesicles by Dicer knock-down in the progenitor cells, or depletion of pro-angiogenic miR-126 and miR-296 by transfection with specific miR-antagomirs. Thus, microvesicles derived from endothelial progenitor cells protect the kidney from ischemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative program.
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Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets.
Cell Transplant
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The efficacy of islet transplantation is limited by poor graft vascularization. We herein demonstrated that microvesicles (MVs) released from endothelial progenitor cells (EPCs) enhanced human islet vascularization. After incorporation into islet endothelium and ?-cells, EPC-derived MVs favored insulin secretion, survival, and revascularization of islets transplanted in SCID mice. MVs induced in vitro islet endothelial cell proliferation, migration, resistance to apoptosis, and organization in vessel-like structures. Moreover, MVs partially overcame the antiangiogenic effect of rapamycin and inhibited endothelial-leukocyte interaction via L-selectin and CD40. MVs were previously shown to contain defined patterns of mRNAs. Here we demonstrated that MVs carried the proangiogenic miR-126 and miR-296 microRNAs (miRNAs). MVs pretreated with RNase or derived from Dicer knocked-down EPCs showed a reduced angiogenic effect. In addition, MVs overcame the antiangiogenic effect of the specific antagomiRs of miR-126 and miR-296, suggesting a relevant contribution of miRNAs delivered by MVs to islet endothelium. Microarray analysis of MV-stimulated islet endothelium indicated the upregulation of mRNAs coding for factors involved in endothelial proliferation, differentiation, and angiogenesis. In addition, MVs induced the activation of the PI3K-Akt and eNOS signaling pathways in islet endothelium. These results suggest that MVs activate an angiogenic program in islet endothelium that may sustain revascularization and ?-cell function.
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Blood pressure variability and cardiovascular autonomic control during hemodialysis in peripheral vascular disease patients.
Physiol Meas
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Hemodialysis (HD) patients with peripheral vascular disease (PVD) are at higher risk of mortality. The main objectives of this work were to investigate the hypothesis of an association between the PVD and an altered control system on peripheral resistance in response to volume depletion induced by HD treatment; and to investigate whether HD induced increase of pulse pressure (PP) is associated with PVD. Continuous blood pressure (BP) was recorded during HD treatment at the beginning and at the end of HD. The overhydration condition was evaluated by means of whole body bioimpedance spectroscopy, measured before each HD treatment. BP variability, heart rate variability and baroreflex sensitivity were then analyzed. Patients affected by PVD reported a prevalence of peripheral local control as shown by higher values of very low frequency in diastolic blood pressure (DBP) variability and a reduced cardiac baroreflex with respect to patients not affected by this pathology. HD treatment induced a significant increase of PP and LF% in DBP series in PVD patients only. Our results suggested that differences in BP variability and PP changes could be related not only to an underlying vascular disease, but also to an alteration in autonomic control.
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Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury.
PLoS ONE
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Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.
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