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Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

Unique Calibrators Derived from Fluorescence-Activated Nanoparticle Sorting for Flow Cytometric Size Estimation of Artificial Vesicles: Possibilities and Limitations.

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Unique Calibrators Derived from Fluorescence-Activated Nanoparticle Sorting for Flow Cytometric Size Estimation of Artificial Vesicles: Possibilities and Limitations.

Cytometry A. 2019 May 23;:

Authors: Simonsen JB, Larsen JB, Hempel C, Eng N, Fossum A, Andresen TL

Abstract
The use of high-throughput flow cytometry to characterize nanoparticles has received increased interest in recent years. However, to fully realize the potential of flow cytometry for the characterization of nanometer-sized objects, suitable calibrators for size estimation must be developed and the sensitivity of conventional flow cytometers has to be advanced. Based on the scattered signal, silica and plastic beads have often been used as flow cytometric size calibrators to evaluate the size of extracellular vesicles and artificial vesicles (liposomes). However, several studies have shown that these beads are unable to accurately correlate scatter intensity to vesicle size. In this work, we present a novel method to estimate the size of individual liposomes in flow cytometry based on liposomal size calibrators prepared by fluorescence-activated cell sorting (FACS), here coined fluorescence-activated nanoparticle sorting (FANS). These calibration liposomes exhibit sizes, structures, and refractive indexes identical to the particles being studied and thus can serve as unique calibrators. First, a sample of polydisperse fluorophore-labeled unilamellar liposomes was prepared and analyzed by flow cytometry. Next, different fractions of the polydisperse liposomes were FANS-sorted according to their fluorescence intensity. Thereafter, we employed nanoparticle tracking analysis (NTA) to evaluate the liposome sizes of the FANS-sorted liposome fractions. Finally, we correlated the flow cytometric readouts (side scatter and fluorescence intensity) of the FANS-sorted liposome fractions with their corresponding size obtained by NTA. This procedure enabled us to translate the liposome fluorescence intensity to the liposome size in nanometers for all detected individual liposomes. We validated the size distribution of our polydisperse liposome sample obtained from flow cytometry in combination with our FANS-calibrators against standard methods for sizing nanoparticles, including NTA and cryo-transmission electron microscopy. This work also highlights the limitation of using the flow cytometric side scattering readout to determine the size of small (30-300 nm) artificial vesicles. © 2019 International Society for Advancement of Cytometry.

PMID: 31120635 [PubMed - as supplied by publisher]

Novel Biomarkers to Assess In-Utero Effects of Maternal Opioid Use: First Steps towards Understanding Short and Long Term Neurodevelopmental Sequelae.

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Novel Biomarkers to Assess In-Utero Effects of Maternal Opioid Use: First Steps towards Understanding Short and Long Term Neurodevelopmental Sequelae.

Genes Brain Behav. 2019 May 23;:

Authors: Goetzl L, Thompson-Felix T, Darbinian N, Merabova N, Merali S, Merali C, Sanserino K, Tatevosian T, Fant B, Wimmer ME

Abstract
Maternal opioid use disorder is common, resulting in significant neonatal morbidity and cost. Currently, it is not possible to predict which opioid-exposed newborns will require pharmacotherapy for neonatal abstinence syndrome. Further, little is known regarding the effects of maternal opioid use disorder on the developing human brain. We hypothesized that novel methodologies utilizing fetal central nervous system-derived extracellular vesicles isolated from maternal blood can address these gaps in knowledge. Plasma from opioid users and controls between 9 and 21 weeks was precipitated and extracellular vesicles were isolated. Mu opioid and cannabinoid receptor levels were quantified. Label free proteomics studies and unbiased small RNA next generation sequencing was performed in paired fetal brain tissue. Maternal opioid use disorder increased mu opioid receptor protein levels in extracellular vesicles independent of opioid equivalent dose. Moreover, cannabinoid receptor levels in extracellular vesicles were upregulated with opioid exposure indicating cross talk with endocannabinoids. Maternal opioid use disorder was associated with significant changes in extracellular vesicle protein cargo and fetal brain micro RNA expression, especially in male fetuses. Many of the altered cargo molecules and micro RNAs identified are associated with adverse clinical neurodevelopmental outcomes. Our data suggest that assays relying on extracellular vesicles isolated from maternal blood extracellular vesicles may provide information regarding fetal response to opioids in the setting of maternal opioid use disorder. Prospective clinical studies are needed to evaluate the association between extracellular vesicle biomarkers, risk of neonatal abstinence syndrome, and neurodevelopmental outcomes.

PMID: 31119847 [PubMed - as supplied by publisher]

Atorvastatin Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells Derived Exosomes in Acute Myocardial Infarction via Up-regulating Long Non-coding RNA H19.

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Atorvastatin Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells Derived Exosomes in Acute Myocardial Infarction via Up-regulating Long Non-coding RNA H19.

Cardiovasc Res. 2019 May 22;:

Authors: Huang P, Wang L, Li Q, Tian X, Xu J, Xu J, Xiong Y, Chen G, Qian H, Jin C, Yu Y, Cheng K, Qian L, Yang Y

Abstract
AIMS: Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms.
METHODS AND RESULTS: Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo), and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and ICAM-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19.
CONCLUSIONS: Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.

PMID: 31119268 [PubMed - as supplied by publisher]

Function of Adipose-Derived Mesenchymal Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension through miR-191 via Regulation of BMPR2.

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Function of Adipose-Derived Mesenchymal Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension through miR-191 via Regulation of BMPR2.

Biomed Res Int. 2019;2019:2858750

Authors: Zhang C, Wang P, Mohammed A, Zhou Z, Zhang S, Ni S, Tang Z

Abstract
Pulmonary arterial hypertension (PAH) is a serious condition. However, prevailing therapeutic strategies are not effective enough to treat PAH. Therefore, finding an effective therapy is clearly warranted. Adipose-derived mesenchymal stem cells (ASCs) and ASCs-derived exosomes (ASCs-Exos) exert protective effects in PAH, but the underlying mechanism remains unclear. Using a coculture of ASCs and monocrotaline pyrrole (MCTP)-treated human pulmonary artery endothelial cells (HPAECs), we demonstrated that ASCs increased cell proliferation in MCTP-treated HPAECs. Results showed that ASCs-Exos improved proliferation of both control HPAECs and MCTP-treated HPAECs. In addition, by transfecting ASCs with antagomir we observed that low exosomal miR-191 expression inhibited HPAECs proliferation whereas the agomir improved. Similar results were observed in vivo using a monocrotaline (MCT)-induced PAH rat model following ASCs transplantation. And ASCs transplantation attenuated MCT-induced PAH albeit less than the antagomir treated group. Finally, we found that miR-191 repressed the expression of bone morphogenetic protein receptor 2 (BMPR2) in HPAECs and PAH rats. Thus, we conjectured that miR-191, in ASCs and ASCs-Exos, plays an important role in PAH via regulation of BMPR2. These findings are expected to contribute to promising therapeutic strategies for treating PAH in the future.

PMID: 31119161 [PubMed - in process]

Exosomes, cancer's little army.

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Exosomes, cancer's little army.

Stem Cell Investig. 2019;6:9

Authors: Al-Sowayan BS, Al-Shareeda AT, Al-Hujaily EM

Abstract
In an attempt to conceptualize the process of cancer formation, Hanahan and Weinberg [2000] have outlined six universal characteristics of tumorigenesis, and labelled them as the "hallmarks of cancer". These hallmarks include; unlimited proliferation, evading growth suppressors, resisting cell death, replicative immortality, inducing angiogenesis, initiating invasion and metastasis. Cancer cell signalling is crucial for initiating and controlling cellular pathways that are involved in these hallmarks. The intricate network of communication between cancer cells and other cancer or non-cancer cells is still being investigated, and is yet to be fully understood. Initially it was proposed that the main form of communication between cells within the tumour microenvironment are soluble growth factors, and gap junctions. Then, researchers reported another form of cell-to-cell communication, through the release of spherical particles called exosomes. It is believed that these exosomes enable communication through the transfer of active components from the releasing cell, and off-loading it into the recipient cell. As researchers continue to examine the development of the cancer hallmarks and the pathways involved, it became evident that cancer cell-derived exosomes play a major role in almost all of them. This review will examine the role played by cancer cell-derived exosomes in development of cancer.

PMID: 31119147 [PubMed]

Exosomes in esophageal cancer: A review on tumorigenesis, diagnosis and therapeutic potential.

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Exosomes in esophageal cancer: A review on tumorigenesis, diagnosis and therapeutic potential.

World J Clin Cases. 2019 Apr 26;7(8):908-916

Authors: Su LL, Chang XJ, Zhou HD, Hou LB, Xue XY

Abstract
Exosomes are nanovesicles secreted from various types of cells and can be isolated from various bodily fluids, such as blood and urine. The number and molecular contents, including proteins and RNA of exosomes, have been shown to reflect their parental cell origins, characteristics and biological behaviors. An increasing number of studies have demonstrated that exosomes play a role in the course of tumorigenesis, diagnosis, treatment and prognosis, although its precise functions in tumors are still unclear. Moreover, owing to a lack of a standard approach, exosomes and its contents have not yet been put into clinical practice successfully. This review aims to summarize the current knowledge on exosomes and its contents in esophageal cancer as well as the current limitations/challenges in its clinical application, which may provide a basis for an all-around understanding of the implementation of exosomes and exosomal contents in the surveillance and therapy of esophageal cancer.

PMID: 31119136 [PubMed]

Osteoblast-Derived Vesicle Protein Content Is Temporally Regulated During Osteogenesis: Implications for Regenerative Therapies.

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Osteoblast-Derived Vesicle Protein Content Is Temporally Regulated During Osteogenesis: Implications for Regenerative Therapies.

Front Bioeng Biotechnol. 2019;7:92

Authors: Davies OG, Cox SC, Azoidis I, McGuinness AJA, Cooke M, Heaney LM, Grover LM

Abstract
Osteoblast-derived extracellular vesicles (EV) are a collection of secreted (sEVs) and matrix-bound nanoparticles that function as foci for mineral nucleation and accumulation. Due to the fact sEVs can be isolated directly from the culture medium of mineralizing osteoblasts, there is growing interest their application regenerative medicine. However, at present therapeutic advancements are hindered by a lack of understanding of their precise temporal contribution to matrix mineralization. This study advances current knowledge by temporally aligning sEV profile and protein content with mineralization status. sEVs were isolated from mineralizing primary osteoblasts over a period of 1, 2, and 3 weeks. Bimodal particle distributions were observed (weeks 1 and 3: 44 and 164 nm; week 2: 59 and 220 nm), indicating a heterogeneous population with dimensions characteristic of exosome- (44 and 59 nm) and microvesicle-like (164 and 220 nm) particles. Proteomic characterization by liquid chromatography tandem-mass spectrometry (LC-MS/MS) revealed a declining correlation in EV-localized proteins as mineralization advanced, with Pearson correlation-coefficients of 0.79 (week 1 vs. 2), 0.6 (2 vs. 3) and 0.46 (1 vs. 3), respectively. Principal component analysis (PCA) further highlighted a time-dependent divergence in protein content as mineralization advanced. The most significant variations were observed at week 3, with a significant (p < 0.05) decline in particle concentration, visual evidence of EV rupture and enhanced mineralization. A total of 116 vesicle-localized proteins were significantly upregulated at week 3 (56% non-specifically, 19% relative to week 1, 25% relative to week 2). Gene ontology enrichment analysis of these proteins highlighted overrepresentation of genes associated with matrix organization. Of note, increased presence of phospholipid-binding and calcium channeling annexin proteins (A2, A5, and A6) indicative of progressive variations in the nucleational capacity of vesicles, as well as interaction with the surrounding ECM. We demonstrate sEV-mediated mineralization is dynamic process with variations in vesicle morphology and protein content having a potential influence on developmental changes matrix organization. These findings have implications for the selection and application of EVs for regenerative applications.

PMID: 31119130 [PubMed]

Circular RNAs as potential biomarkers and therapeutics for cardiovascular disease.

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Circular RNAs as potential biomarkers and therapeutics for cardiovascular disease.

PeerJ. 2019;7:e6831

Authors: Wang W, Wang Y, Piao H, Li B, Huang M, Zhu Z, Li D, Wang T, Xu R, Liu K

Abstract
Circular RNAs (circRNAs) are genetic regulators that were earlier considered as "junk". In contrast to linear RNAs, they have covalently linked ends with no polyadenylated tails. CircRNAs can act as RNA-binding proteins, sequestering agents, transcriptional regulators, as well as microRNA sponges. In addition, it is reported that some selected circRNAs are transformed into functional proteins. These RNA molecules always circularize through covalent bonds, and their presence has been demonstrated across species. They are usually abundant and stable as well as evolutionarily conserved in tissues (liver, lung, stomach), saliva, exosomes, and blood. Therefore, they have been proposed as the "next big thing" in molecular biomarkers for several diseases, particularly in cancer. Recently, circRNAs have been investigated in cardiovascular diseases (CVD) and reported to play important roles in heart failure, coronary artery disease, and myocardial infarction. Here, we review the recent literature and discuss the impact and the diagnostic and prognostic values of circRNAs in CVD.

PMID: 31119072 [PubMed]

Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium.

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Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium.

Sci Transl Med. 2019 May 22;11(493):

Authors: Saha P, Sharma S, Korutla L, Datla SR, Shoja-Taheri F, Mishra R, Bigham GE, Sarkar M, Morales D, Bittle G, Gunasekaran M, Ambastha C, Arfat MY, Li D, Habertheuer A, Hu R, Platt MO, Yang P, Davis ME, Vallabhajosyula P, Kaushal S

Abstract
The stem cell field is hindered by its inability to noninvasively monitor transplanted cells within the target organ in a repeatable, time-sensitive, and condition-specific manner. We hypothesized that quantifying and characterizing transplanted cell-derived exosomes in the recipient plasma would enable reliable, noninvasive surveillance of the conditional activity of the transplanted cells. To test this hypothesis, we used a human-into-rat xenogeneic myocardial infarction model comparing two well-studied progenitor cell types: cardiosphere-derived cells (CDCs) and c-kit+ cardiac progenitor cells (CPCs), both derived from the right atrial appendage of adults undergoing cardiopulmonary bypass. CPCs outperformed the CDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of transplanted CDCs or CPCs in vivo, we purified progenitor cell-specific exosomes from recipient total plasma exosomes. Seven days after transplantation, the concentration of plasma CPC-specific exosomes increased about twofold compared to CDC-specific exosomes. Computational pathway analysis failed to link CPC or CDC cellular messenger RNA (mRNA) with observed myocardial recovery, although recovery was linked to the microRNA (miRNA) cargo of CPC exosomes purified from recipient plasma. We further identified mechanistic pathways governing specific outcomes related to myocardial recovery associated with transplanted CPCs. Collectively, these findings demonstrate the potential of circulating progenitor cell-specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted cells. These data implicate the surveillance potential of cell-specific exosomes for allogeneic cell therapies.

PMID: 31118291 [PubMed - in process]

Extracellular Vesicles and their miRNA Cargo: A Means of Communication between Soma and Germline in the Mammalian Reproductive System.

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Extracellular Vesicles and their miRNA Cargo: A Means of Communication between Soma and Germline in the Mammalian Reproductive System.

Chimia (Aarau). 2019 May 29;73(6):356-361

Authors: Maciel E, Mansuy IM

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs able to silence gene expression by RNA interference. They are present in cells but many are contained in extracellular vesicles (EVs) that can be released by cells in the circulation. Circulating EVs can encounter other cells in the body and deliver their miRNA cargo. This process enables long-range communication between different cells and has been proposed to play important physiological roles. One of these roles that remains less well studied is in the reproductive system. In ovaries and testes, constant communication between somatic cells and developing germ cells is necessary for their maturation and EVs have been proposed to contribute to this communication. EVs might also enable external factors derived from environmental exposure to reach gametes and keep a trace of exposure for the offspring.

PMID: 31118116 [PubMed - in process]

Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli.

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Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli.

Biol Sex Differ. 2019 May 22;10(1):26

Authors: Hunter LW, Jayachandran M, Miller VM

Abstract
BACKGROUND: There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated by inflammatory and thrombotic factors have the potential to disrupt endothelial cells of the brain microvasculature. Therefore, experiments were designed to identify sex differences in the phenotype of MV released from cultured human brain microvascular endothelial cells (HBMEC) in response to inflammatory and thrombotic stimuli.
METHODS: Cultured HBMEC derived from 20- to 30-year-old male and female donors were treated for 20 h with medium supplemented with tumor necrosis factor alpha (TNFα; 20 ng/ml), thrombin (THR; 2 U/ml), or vehicle (i.e., control). MV were isolated from the conditioned media by high-speed centrifugation and quantified by digital flow cytometry by labeling with fluorophore-conjugated primary antibodies against PECAM-1, integrin αvβ3, ICAM-1, E-selectin, or MCAM. In addition, temporal uptake of labeled MV into control HBMEC was examined by confocal microscopy.
RESULTS: Under control conditions, male HBMEC released fewer MV expressing each antigen, except for PECAM-1, than female cells (P < 0.05). Neither TNFα nor THR reduced cell viability. However, TNFα induced apoptosis in female and male cells, whereas THR increased apoptosis marginally only in male cells. TNFα increased expression of all antigens tested on MV in male cells, but only increased expression of integrin αvβ3, ICAM-1, and E-selectin on MV from female cells. THR increased expression of PECAM-1, ICAM-1, and MCAM-1 on MV from male but not female cells. MV were internalized and localized to lysosomes within 90 min after their application to HBMEC.
CONCLUSIONS: There are sex differences in expression of cell adhesion molecules on MV released from HBMEC under control conditions and upon activation by TNFα or THR. MV taken up by unstimulated HBMEC may impact the integrity of the brain microvasculature and account, in part, for sex differences in vascular pathologies in the brain.

PMID: 31118073 [PubMed - in process]

Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders.

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Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders.

ACS Nano. 2019 May 22;:

Authors: Riazifar M, Mohammadi MR, Pone EJ, Yeri A, Lässer C, Segaliny AI, McIntyre LL, Shelke GV, Hutchins E, Hamamoto A, Calle EN, Crescitelli R, Liao W, Pham V, Yin Y, Jayaraman J, Lakey JR, Walsh CM, Van Keuren-Jensen K, Lotvall J, Zhao W

Abstract
To dissect therapeutic mechanisms of transplanted stem cells and develop exosome-based nanotherapeutics in treating autoimmune and neurodegenerative diseases, we assessed the effect of exosomes secreted from human mesenchymal stem cells (MSCs) in treating multiple sclerosis using an experimental autoimmune encephalomyelitis (EAE) mouse model. We found that intravenous administration of exosomes produced by MSCs stimulated by IFNγ (IFNγ-Exo) i) reduced the mean clinical score of EAE mice compared to PBS control, ii) reduced demyelination, iii) decreased neuroinflammation, and iv) upregulated the number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords of EAE mice. Co-culture of IFNγ-Exo with activated PBMC cells in vitro reduced PBMC proliferation and levels of proinflammatory Th1 and Th17 cytokines including IL-6, IL-12p70, IL-17AF, and IL-22 yet increased level of immunosuppressive cytokine indoleamine 2,3-dioxygenase (IDO). IFNγ-Exo could also induce Tregs in vitro in murine splenocyte culture, likely mediated by a third-party accessory cell type. Further IFNγ-Exo characterization by deep RNA sequencing suggested that IFNγ-Exo contain anti-inflammatory RNAs, where their inactivation partially hindered the exosomes potential to induce Tregs. Furthermore, we found that IFNγ-Exo harbors multiple anti-inflammatory and neuroprotective proteins. These results not only shed light on stem cell therapeutic mechanism, but also provide evidence that MSC-derived exosomes can potentially serve as cell-free therapies in creating a tolerogenic immune response to treat autoimmune and central nervous system disorders.

PMID: 31117376 [PubMed - as supplied by publisher]

 

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