The Experts below are selected from a list of 14856 Experts worldwide ranked by ideXlab platform
David S. Allan - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell derived Microvesicles
Stem Cell Reviews and Reports, 2015Co-Authors: Celine Akyurekli, Yevgeniya Le, Dean Fergusson, David S. Allan, Richard B RichardsonAbstract:Background The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in Microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy.
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A Systematic Review of Preclinical Studies on the Therapeutic Potential of Mesenchymal Stromal Cell-Derived Microvesicles
Stem Cell Reviews and Reports, 2015Co-Authors: Celine Akyurekli, Yevgeniya Le, Dean Fergusson, Jason Tay, Richard B Richardson, David S. AllanAbstract:BACKGROUND: The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in Microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy.\n\nMETHODS: A total of 190 published articles were identified in our systematic search of electronic databases (MEDLINE, EMBASE, PUBMED). After screening for eligibility, a total of 17 controlled studies testing MSC-derived MVs as therapeutic interventions in animal models of disease underwent comprehensive review, quality assessment, and data extraction.\n\nRESULTS: Thirteen studies addressed the regenerative potential following organ injury. Six studies were included on acute kidney injury, 4 on myocardial infarction and reperfusion injury, 1 on hind limb ischemia, 1 on liver injury, and 1 on hypoxic lung injury. Four studies addressed immunological effects of MSC-derived MVs on inhibiting tumor growth. Twelve studies (71 %) provided explicit information regarding the number of animals allocated to treatment or control groups. Five studies (29 %) randomly assigned animals to treatment or control groups and only 1 study (6 %) reported on blinding. Therapeutic intervention involved isolation of exosomes (40-100 nm) in eight studies, while nine studies tested unfractionated Microvesicles (
James W. Clancy - One of the best experts on this subject based on the ideXlab platform.
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Biology and biogenesis of shed Microvesicles
Small GTPases, 2016Co-Authors: Christopher J. Tricarico, James W. Clancy, Crislyn D'souza-schoreyAbstract:ABSTRACTThe ability of cells to transmit bioactive molecules to recipient cells and the extracellular environment is a fundamental requirement for both normal physiology and disease pathogenesis. It has traditionally been thought that soluble factors released from cells were responsible for this cellular signaling but recent research has revealed a fundamental role for Microvesicles in this process. Microvesicles are heterogeneous membrane-bound sacs that are shed from the surface of cells into the extracellular environment in a highly regulated process. They are shed following the selective incorporation of a host of molecular cargo including multiple types of proteins and nucleic acids. In addition to providing new insight into the etiology of complex human diseases, Microvesicles also show great promise as a tool for advanced diagnosis and therapy as we move forward into a new age of personalized medicine. Here we review current status of the rapidly evolving field of microvesicle biology, highlighting...
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Regulated delivery of molecular cargo to invasive tumour-derived Microvesicles
Nature Communications, 2015Co-Authors: James W. Clancy, Alanna Sedgwick, Carine Rosse, Vandhana Muralidharan-chari, Graca Raposo, Michael Method, Philippe Chavrier, Crislyn D'souza-schoreyAbstract:Cells release multiple, distinct forms of extracellular vesicles including structures known as Microvesicles, which are known to alter the extracellular environment. Despite growing understanding of microvesicle biogenesis, function and contents, mechanisms regulating cargo delivery and enrichment remain largely unknown. Here we demonstrate that in amoeboid-like invasive tumour cell lines, the v-SNARE, VAMP3, regulates delivery of microvesicle cargo such as the membrane-type 1 matrix metalloprotease (MT1-MMP) to shedding Microvesicles. MT1-MMP delivery to nascent Microvesicles depends on the association of VAMP3 with the tetraspanin CD9 and facilitates the maintenance of amoeboid cell invasion. VAMP3-shRNA expression depletes shed vesicles of MT1-MMP and decreases cell invasiveness when embedded in cross-linked collagen matrices. Finally, we describe functionally similar Microvesicles isolated from bodily fluids of ovarian cancer patients. Together these studies demonstrate the importance of microvesicle cargo sorting in matrix degradation and disease progression.
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tumor derived Microvesicles shedding light on novel microenvironment modulators and prospective cancer biomarkers
Genes & Development, 2012Co-Authors: Crislyn Dsouzaschorey, James W. ClancyAbstract:Recent advances in the study of tumor-derived Microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived Microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. The complexity of their bioactive cargo—which includes proteins, RNA, microRNA, and DNA—suggests multipronged mechanisms by which Microvesicles can condition the extracellular milieu to facilitate disease progression. The formation of these shed vesicles likely involves both a redistribution of surface lipids and the vertical trafficking of cargo to sites of microvesicle biogenesis at the cell surface. Current research also suggests that molecular profiling of these structures could unleash their potential as circulating biomarkers as well as platforms for personalized medicine. Thus, new and improved strategies for microvesicle identification, isolation, and capture will have marked implications in point-of-care diagnostics for cancer patients.
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Microvesicles mediators of extracellular communication during cancer progression
Journal of Cell Science, 2010Co-Authors: Vandhana Muralidharanchari, James W. Clancy, Alanna Sedgwick, Crislyn DsouzaschoreyAbstract:Microvesicles are generated by the outward budding and fission of membrane vesicles from the cell surface. Recent studies suggest that microvesicle shedding is a highly regulated process that occurs in a spectrum of cell types and, more frequently, in tumor cells. Microvesicles have been widely detected in various biological fluids including peripheral blood, urine and ascitic fluids, and their function and composition depend on the cells from which they originate. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, they are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, and stem-cell renewal and expansion. This Commentary summarizes recent literature on the properties and biogenesis of Microvesicles and their potential role in cancer progression.
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arf6 regulated shedding of tumor cell derived plasma membrane Microvesicles
Current Biology, 2009Co-Authors: Vandhana Muralidharanchari, James W. Clancy, Graca Raposo, Philippe Chavrier, Carolyn Plou, Maryse Romao, Crislyn DsouzaschoreyAbstract:Summary Background Increased mitogen-activated protein kinase (MAPK) signaling, small GTPase activation, cytoskeletal rearrangements, and the directed targeting of proteases to sites of extracellular matrix degradation all accompany the process of tumor cell invasion. Several studies have implicated the small GTP-binding protein ARF6 in tumor cell invasion, although the molecular basis by which ARF6 facilitates this process is unclear. Results We show that the ARF6 GTP/GDP cycle regulates the release of protease-loaded plasma membrane-derived Microvesicles from tumor cells into the surrounding environment. To enable microvesicle shedding, ARF6-GTP-dependent activation of phospholipase D promotes the recruitment of the extracellular signal-regulated kinase (ERK) to the plasma membrane where, in turn, ERK phosphorylates and activates myosin light-chain kinase (MLCK). MLCK-mediated MLC phosphorylation is required for microvesicle release. Inhibition of ARF6 activation is accompanied by PKC-mediated phosphorylation of MLC, which blocks microvesicle shedding. Protein cargo appears to be selectively sorted into Microvesicles, and adhesion to the extracellular matrix (ECM) is facilitated by microvesicle-associated integrin receptors. Conclusions Microvesicle shedding in tumor cells occurs via an actomyosin-based membrane abscission mechanism that is regulated by nucleotide cycling on ARF6. Microvesicle shedding appears to release selected cellular components, particularly those involved in cell adhesion and motility, into the surrounding environment. These findings suggest that ARF6 activation and the proteolytic activities of Microvesicles, both of which are thought to correlate directly with tumor progression, could potentially serve as biomarkers for disease.
Crislyn Dsouzaschorey - One of the best experts on this subject based on the ideXlab platform.
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tumor derived Microvesicles shedding light on novel microenvironment modulators and prospective cancer biomarkers
Genes & Development, 2012Co-Authors: Crislyn Dsouzaschorey, James W. ClancyAbstract:Recent advances in the study of tumor-derived Microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived Microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. The complexity of their bioactive cargo—which includes proteins, RNA, microRNA, and DNA—suggests multipronged mechanisms by which Microvesicles can condition the extracellular milieu to facilitate disease progression. The formation of these shed vesicles likely involves both a redistribution of surface lipids and the vertical trafficking of cargo to sites of microvesicle biogenesis at the cell surface. Current research also suggests that molecular profiling of these structures could unleash their potential as circulating biomarkers as well as platforms for personalized medicine. Thus, new and improved strategies for microvesicle identification, isolation, and capture will have marked implications in point-of-care diagnostics for cancer patients.
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Microvesicles mediators of extracellular communication during cancer progression
Journal of Cell Science, 2010Co-Authors: Vandhana Muralidharanchari, James W. Clancy, Alanna Sedgwick, Crislyn DsouzaschoreyAbstract:Microvesicles are generated by the outward budding and fission of membrane vesicles from the cell surface. Recent studies suggest that microvesicle shedding is a highly regulated process that occurs in a spectrum of cell types and, more frequently, in tumor cells. Microvesicles have been widely detected in various biological fluids including peripheral blood, urine and ascitic fluids, and their function and composition depend on the cells from which they originate. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, they are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, and stem-cell renewal and expansion. This Commentary summarizes recent literature on the properties and biogenesis of Microvesicles and their potential role in cancer progression.
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arf6 regulated shedding of tumor cell derived plasma membrane Microvesicles
Current Biology, 2009Co-Authors: Vandhana Muralidharanchari, James W. Clancy, Graca Raposo, Philippe Chavrier, Carolyn Plou, Maryse Romao, Crislyn DsouzaschoreyAbstract:Summary Background Increased mitogen-activated protein kinase (MAPK) signaling, small GTPase activation, cytoskeletal rearrangements, and the directed targeting of proteases to sites of extracellular matrix degradation all accompany the process of tumor cell invasion. Several studies have implicated the small GTP-binding protein ARF6 in tumor cell invasion, although the molecular basis by which ARF6 facilitates this process is unclear. Results We show that the ARF6 GTP/GDP cycle regulates the release of protease-loaded plasma membrane-derived Microvesicles from tumor cells into the surrounding environment. To enable microvesicle shedding, ARF6-GTP-dependent activation of phospholipase D promotes the recruitment of the extracellular signal-regulated kinase (ERK) to the plasma membrane where, in turn, ERK phosphorylates and activates myosin light-chain kinase (MLCK). MLCK-mediated MLC phosphorylation is required for microvesicle release. Inhibition of ARF6 activation is accompanied by PKC-mediated phosphorylation of MLC, which blocks microvesicle shedding. Protein cargo appears to be selectively sorted into Microvesicles, and adhesion to the extracellular matrix (ECM) is facilitated by microvesicle-associated integrin receptors. Conclusions Microvesicle shedding in tumor cells occurs via an actomyosin-based membrane abscission mechanism that is regulated by nucleotide cycling on ARF6. Microvesicle shedding appears to release selected cellular components, particularly those involved in cell adhesion and motility, into the surrounding environment. These findings suggest that ARF6 activation and the proteolytic activities of Microvesicles, both of which are thought to correlate directly with tumor progression, could potentially serve as biomarkers for disease.
Xandra O Breakefield - One of the best experts on this subject based on the ideXlab platform.
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rna expression patterns in serum Microvesicles from patients with glioblastoma multiforme and controls
BMC Cancer, 2012Co-Authors: Mikkel Noerholm, Leonora Balaj, Tobias Limperg, Afshin Salehi, Fred H Hochberg, Xandra O Breakefield, Bob S CarterAbstract:Background RNA from exosomes and other Microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients.
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Gesicles: Microvesicle “Cookies” for Transient Information Transfer Between Cells
Molecular Therapy, 2011Co-Authors: Xandra O Breakefield, Robert M Frederickson, Richard J. SimpsonAbstract:Readers who have spent much time peering at cultured cells through a microscope may have noticed the membranous debris that accumulates in the culture medium over time. We now know that this “debris” actually comprises components of an elaborate intercellular communication system mediated by membranous extracellular organelles collectively called Microvesicles. Given their capacity to transmit information between cells, the types, contents, and functions of these Microvesicles are being studied for various applications in many fields. Although a number of reports have shown that proteins overexpressed in cells are incorporated into Microvesicles derived from them, their potential for directed informational protein delivery is just now being explored. In this issue of Molecular Therapy, Mangeot et al.1 document microvesicle-mediated transfer of two different proteins that are able to temporarily manipulate the phenotype of the recipient cells. The Microvesicles were generated by expression of the spike glycoprotein of vesicular stomatitis virus (VSV-G), which stimulates their production. The authors coined the term “gesicles” to describe the modified Microvesicles, which represent an important new functional twist in the expanding and diverse armamentarium of molecular information transfer for therapeutic and experimental applications.
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brain tumor Microvesicles insights into intercellular communication in the nervous system
Cellular and Molecular Neurobiology, 2011Co-Authors: Leonora Balaj, Johan Skog, Xandra O BreakefieldAbstract:Brain tumors are heterogeneous tumors composed of differentiated tumor cells that resemble various neural cells and a small number of multipotent cancer stem cells. These tumors modify normal cells in their environment to promote tumor growth, invasion and metastases by various ways. Recent publications show that glioblastoma cells release Microvesicles that contain a select subset of cellular proteins and RNAs. These Microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, Microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA. This commentary explores the recent advances in this novel intercellular communication route and discusses the potential physiological role of Microvesicles in brain tumorigenesis.
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tumour Microvesicles contain retrotransposon elements and amplified oncogene sequences
Nature Communications, 2011Co-Authors: Leonora Balaj, Xandra O Breakefield, Ryan T Lessard, Scott L Pomeroy, Johan SkogAbstract:Tumour cells release an abundance of Microvesicles containing a selected set of proteins and RNAs. Here, we show that tumour Microvesicles also carry DNA, which reflects the genetic status of the tumour, including amplification of the oncogene c-Myc. We also find amplified c-Myc in serum Microvesicles from tumour-bearing mice. Further, we find remarkably high levels of retrotransposon RNA transcripts, especially for some human endogenous retroviruses, such as LINE-1 and Alu retrotransposon elements, in tumour Microvesicles and these transposable elements could be transferred to normal cells. These findings expand the nucleic acid content of tumour Microvesicles to include: elevated levels of specific coding and non-coding RNA and DNA, mutated and amplified oncogene sequences and transposable elements. Thus, tumour Microvesicles contain a repertoire of genetic information available for horizontal gene transfer and potential use as blood biomarkers for cancer.
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microfluidic isolation and transcriptome analysis of serum Microvesicles
Lab on a Chip, 2010Co-Authors: Chihchen Chen, Leonora Balaj, Xandra O Breakefield, Bob S Carter, Johan Skog, Ryan T Lessard, Thomas Wurdinger, Mehmet Toner, Daniel IrimiaAbstract:Microvesicles (exosomes) shed from both normal and cancerous cells may serve as means of intercellular communication. These Microvesicles carry proteins, lipids and nucleic acids derived from the host cell. Their isolation and analysis from blood samples have the potential to provide information about state and progression of malignancy and should prove of great clinical importance as biomarkers for a variety of disease states. However, current protocols for isolation of Microvesicles from blood require high-speed centrifugation and filtration, which are cumbersome and time consuming. In order to take full advantage of the potential of Microvesicles as biomarkers for clinical applications, faster and simpler methods of isolation will be needed. In this paper, we present an easy and rapid microfluidic immunoaffinity method to isolate Microvesicles from small volumes of both serum from blood samples and conditioned medium from cells in culture. RNA of high quality can be extracted from these Microvesicles providing a source of information about the genetic status of tumors to serve as biomarkers for diagnosis and prognosis of cancer.
Johan Skog - One of the best experts on this subject based on the ideXlab platform.
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brain tumor Microvesicles insights into intercellular communication in the nervous system
Cellular and Molecular Neurobiology, 2011Co-Authors: Leonora Balaj, Johan Skog, Xandra O BreakefieldAbstract:Brain tumors are heterogeneous tumors composed of differentiated tumor cells that resemble various neural cells and a small number of multipotent cancer stem cells. These tumors modify normal cells in their environment to promote tumor growth, invasion and metastases by various ways. Recent publications show that glioblastoma cells release Microvesicles that contain a select subset of cellular proteins and RNAs. These Microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, Microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA. This commentary explores the recent advances in this novel intercellular communication route and discusses the potential physiological role of Microvesicles in brain tumorigenesis.
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tumour Microvesicles contain retrotransposon elements and amplified oncogene sequences
Nature Communications, 2011Co-Authors: Leonora Balaj, Xandra O Breakefield, Ryan T Lessard, Scott L Pomeroy, Johan SkogAbstract:Tumour cells release an abundance of Microvesicles containing a selected set of proteins and RNAs. Here, we show that tumour Microvesicles also carry DNA, which reflects the genetic status of the tumour, including amplification of the oncogene c-Myc. We also find amplified c-Myc in serum Microvesicles from tumour-bearing mice. Further, we find remarkably high levels of retrotransposon RNA transcripts, especially for some human endogenous retroviruses, such as LINE-1 and Alu retrotransposon elements, in tumour Microvesicles and these transposable elements could be transferred to normal cells. These findings expand the nucleic acid content of tumour Microvesicles to include: elevated levels of specific coding and non-coding RNA and DNA, mutated and amplified oncogene sequences and transposable elements. Thus, tumour Microvesicles contain a repertoire of genetic information available for horizontal gene transfer and potential use as blood biomarkers for cancer.
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nucleic acids within urinary exosomes Microvesicles are potential biomarkers for renal disease
Kidney International, 2010Co-Authors: Kevin C Miranda, Daniel T Bond, Mary Mckee, Johan Skog, Teodor G Păunescu, Nicolas Da Silva, Dennis Brown, Leileata M RussoAbstract:Urinary exosomes or Microvesicles are being studied intensively to identify potential new biomarkers for renal disease. We sought to identify whether these Microvesicles contain nucleic acids. We isolated Microvesicles from human urine in the same density range as that previously described for urinary exosomes and found them to have an RNA integrity profile similar to that of kidney tissue, including 18S and 28S rRNA. This profile was better preserved in urinary Microvesicles compared with whole cells isolated from urine, suggesting that Microvesicles may protect RNA during urine passage. We were able to detect mRNA in the human urinary Microvesicles encoding proteins from all regions of the nephron and the collecting duct. Further, to provide a proof of principle, we found that Microvesicles isolated from the urine of the V-ATPase B1 subunit knockout mice lacked mRNA of this subunit while containing a normal amount of the B2 subunit and aquaporin 2. The Microvesicles were found to be contaminated with extraneous DNA potentially on their surface; therefore, we developed a rapid and reliable means to isolate nucleic acids from within urine Microvesicles devoid of this extraneous contamination. Our study provides an experimental strategy for the routine isolation and use of urinary Microvesicles as a novel and non-invasive source of nucleic acids to further renal disease biomarker discovery.
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microfluidic isolation and transcriptome analysis of serum Microvesicles
Lab on a Chip, 2010Co-Authors: Chihchen Chen, Leonora Balaj, Xandra O Breakefield, Bob S Carter, Johan Skog, Ryan T Lessard, Thomas Wurdinger, Mehmet Toner, Daniel IrimiaAbstract:Microvesicles (exosomes) shed from both normal and cancerous cells may serve as means of intercellular communication. These Microvesicles carry proteins, lipids and nucleic acids derived from the host cell. Their isolation and analysis from blood samples have the potential to provide information about state and progression of malignancy and should prove of great clinical importance as biomarkers for a variety of disease states. However, current protocols for isolation of Microvesicles from blood require high-speed centrifugation and filtration, which are cumbersome and time consuming. In order to take full advantage of the potential of Microvesicles as biomarkers for clinical applications, faster and simpler methods of isolation will be needed. In this paper, we present an easy and rapid microfluidic immunoaffinity method to isolate Microvesicles from small volumes of both serum from blood samples and conditioned medium from cells in culture. RNA of high quality can be extracted from these Microvesicles providing a source of information about the genetic status of tumors to serve as biomarkers for diagnosis and prognosis of cancer.
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glioblastoma Microvesicles transport rna and proteins that promote tumour growth and provide diagnostic biomarkers
Nature Cell Biology, 2008Co-Authors: Johan Skog, Bob S Carter, Thomas Wurdinger, Dimphna H Meijer, L Gainche, Miguel Senaesteves, William T Curry, Anna M Krichevsky, Xandra O BreakefieldAbstract:Human glioblastoma cells release Microvesicles containing a diverse set of proteins, miRNAs and mRNAs, which can be taken up by normal host cells that translate the mRNA. Glioma-derived Microvesicles carrying the specific tumour markers EGFRvIII and miRNA-21 promote cell proliferation and may serve as a diagnostic tool.
