scholarly journals Biodistribution, Uptake and Effects Caused by Cancer-Derived Extracellular Vesicles

2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Lilite Sadovska ◽  
Cristina Bajo Santos ◽  
Zane Kalniņa ◽  
Aija Linē
Keyword(s):  
Extracellular Vesicles ◽  
Cell Types ◽  
Cell Phenotype ◽  
Chromosomal Dna ◽  
Metastatic Niche ◽  
Paracrine Signalling ◽  
Cancerous Cell ◽  
The Impact

Extracellular vesicles (EVs) have recently emerged as important mediators of intercellular communication. They are released in the extracellular space by a variety of normal and cancerous cell types and have been found in all human body fluids. Cancer-derived EVs have been shown to carry lipids, proteins, mRNAs, non-coding and structural RNAs and even extra-chromosomal DNA, which can be taken up by recipient cells and trigger diverse physiological and pathological responses. An increasing body of evidence suggests that cancer-derived EVs mediate paracrine signalling between cancer cells. This leads to the increased invasiveness, proliferation rate and chemoresistance, as well as the acquisition of the cancer stem cell phenotype. This stimulates angiogenesis and the reprogramming of normal stromal cells into cancer-promoting cell types. Furthermore, cancer-derived EVs contribute to the formation of the pre-metastatic niche and modulation of anti-tumour immune response. However, as most of these data are obtained by in vitro studies, it is not entirely clear which of these effects are recapitulated in vivo. In the current review, we summarize studies that assess the tissue distribution, trafficking, clearance and uptake of cancer-derived EVs in vivo and discuss the impact they have, both locally and systemically.

scholarly journals The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol

2021 ◽  
Vol 1 (1) ◽  
pp. 84-95
Author(s):  
Patience O. Obi ◽  
Jennifer E. Kent ◽  
Maya M. Jeyaraman ◽  
Nicole Askin ◽  
Taiana M. Pierdoná ◽  
...  
Keyword(s):  
Systematic Review ◽  
Extracellular Vesicles ◽  
Current Knowledge ◽  
Grey Literature ◽  
Specific Treatment ◽  
Therapeutic Effects ◽  
Management Options ◽  
Paracrine Signalling

Asthma is the most common pediatric disease, characterized by chronic airway inflammation and airway hyperresponsiveness. There are several management options for asthma, but no specific treatment. Extracellular vesicles (EVs) are powerful cellular mediators of endocrine, autocrine and paracrine signalling, and can modulate biophysiological function in vitro and in vivo. A thorough investigation of therapeutic effects of EVs in asthma has not been conducted. Therefore, this systematic review is designed to synthesize recent literature on the therapeutic effects of EVs on physiological and biological outcomes of asthma in pre-clinical studies. An electronic search of Web of Science, EMBASE, MEDLINE, and Scopus will be conducted on manuscripts published in the last five years that adhere to standardized guidelines for EV research. Grey literature will also be included. Two reviewers will independently screen the selected studies for title and abstract, and full text based on the eligibility criteria. Data will be extracted, narratively synthesized and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This systematic review will summarize the current knowledge from preclinical studies investigating the therapeutic effects of EVs on asthma. The results will delineate whether EVs can mitigate biological hallmarks of asthma, and if so, describe the underlying mechanisms involved in the process. This insight is crucial for identifying key pathways that can be targeted to alleviate the burden of asthma. The data will also reveal the origin, dosage and biophysical characteristics of beneficial EVs. Overall, our results will provide a scaffold for future intervention and translational studies on asthma treatment.

scholarly journals Postprandial transfer of colostral extracellular vesicles and their protein and miRNA cargo in neonatal calves

2019 ◽  
Author(s):  
Benedikt Kirchner ◽  
Dominik Buschmann ◽  
Vijay Paul ◽  
Michael W. Pfaffl
Keyword(s):  
Extracellular Vesicles ◽  
Expression Profiles ◽  
Bovine Milk ◽  
Cell Types ◽  
Specific Protein ◽  
In Vivo Experiments ◽  
Neonatal Calves ◽  
Almost All

Abstract Background Extracellular vesicles (EVs) such as exosomes are key regulators of intercellular communication that can be found in almost all bio fluids. Although studies in the last decade have made great headway in discerning the role of EVs in many physiological and pathophysiological processes, the bioavailability and impact of dietary EVs and their cargo still remain to be elucidated. Due to its widespread consumption and high content of EV-associated microRNAs and proteins, a major focus in this field has been set on EVs in bovine milk and colostrum. Despite promising in vitro studies in recent years that show high resiliency of milk EVs to degradation and uptake of milk EV cargo in a variety of intestinal and blood cell types, in vivo experiments continue to be inconclusive and sometimes outright contradictive. Results To resolve this discrepancy, we assessed the potential postprandial transfer of colostral EVs to the circulation of newborn calves by analysing colostrum-specific protein and miRNAs, including specific isoforms (isomiRs) in cells, EV isolations and unfractionated samples from blood and colostrum. Our findings reveal distinct populations of EVs in colostrum and blood from cows that can be clearly separated by density, particle concentration and protein content (BTN1A1, MFGE8). Postprandial blood samples of calves show a time-dependent increase in EVs that share morphological and protein characteristics of colostral EVs. Analysis of miRNA expression profiles by Next-Generation Sequencing gave a different picture however. Although significant postprandial expression changes could only be detected for calf EV samples, expression profiles show very limited overlap with highly expressed miRNAs in colostral EVs or colostrum in general. Conclusions Taken together our results indicate a selective uptake of membrane-associated protein cargo but not luminal miRNAs from colostral EVs into the circulation of neonatal calves.

scholarly journals Lipopolysaccharide administration alters extracellular vesicles in human lung-cancer cells and mice

2020 ◽  
Author(s):  
Leandra B. Jones ◽  
Sanjay Kumar ◽  
Courtnee’ R. Bell ◽  
Brennetta J. Crenshaw ◽  
Mamie T. Coats ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Bacterial Infection ◽  
Cell Line ◽  
Extracellular Vesicles ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Diagnostic Tools ◽  
The Impact

AbstractExtracellular vesicles (EVs) play a fundamental role in cell and infection biology and have the potential to act as biomarkers for novel diagnostic tools. In this study, we explored the in vitro impact of bacterial lipopolysaccharide administration on a cell line that represents a target for bacterial infection in the host. Administration of lipopolysaccharide at varying concentrations to this A549 cell line caused only modest changes in cell death, but EV numbers were significantly changed. After treatment with the highest concentration of lipopolysaccharide, EVs derived from A549 cells packaged significantly less interleukin-6 and lysosomal-associated membrane protein 1. We also examined the impact of lipopolysaccharide administration on exosome biogenesis and cargo composition in BALB/c mice. Serum-isolated EVs from lipopolysaccharide-treated mice showed significantly increased lysosomal-associated membrane protein 1 and toll-like receptor 4 levels compared with EVs from control mice. In summary, this study demonstrated that EV numbers and cargo were altered using these in vitro and in vivo models of bacterial infection.

scholarly journals Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis

2021 ◽  
Vol 23 (1) ◽  
pp. 126
Author(s):  
Alasdair G. Kay ◽  
Kane Treadwell ◽  
Paul Roach ◽  
Rebecca Morgan ◽  
Rhys Lodge ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Histopathological Analysis ◽  
Therapeutic Effects ◽  
Synovial Joint ◽  
Paracrine Signalling

Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.

scholarly journals CurvChip - chip platform for investigating cell responses to curved surface features

2018 ◽  
Vol 4 (1) ◽  
pp. 453-456
Author(s):  
Ralf Kemkemer ◽  
Kerstin Frey ◽  
Alena Fischer ◽  
Rumen Krastev
Keyword(s):  
Low Cost ◽  
Cell Types ◽  
Cell Responses ◽  
Surface Topographies ◽  
Sharp Edges ◽  
Pdms Molding ◽  
The Impact ◽  
Thermal Reflow

AbstractSurface topographies are often discussed as an important parameter influencing basic cell behavior. Whereas most in-vitro studies deal with microstructures with sharp edges, smooth, curved microscale topographies might be more relevant concerning in-vivo situations. Addressing the lack of highly defined surfaces with varying curvature, we present a topography chip system with 3D curved features of varying spacing, curvature radii as well as varying overall dimensions of curved surfaces. The CurvChip is produced by low-cost photolithography with thermal reflow, subsequent (repetitive) PDMS molding and hot embossing. The platform facilitates the systematic invitro investigation of the impact of substrate curvature on cell types like epithelial, endothelial, smooth muscle cells, or stem cells. Such investigations will not only help to further understand the mechanism of curvature sensation but may also contribute to optimize cellmaterial interactions in the field of regenerative medicine.

scholarly journals Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

2021 ◽  
Vol 9 ◽  
Author(s):  
Mariana A. Antunes ◽  
Cassia L. Braga ◽  
Tainá B. Oliveira ◽  
Jamil Z. Kitoko ◽  
Ligia L. Castro ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Chronic Obstructive ◽  
Severe Emphysema ◽  
Arginase 1 ◽  
The Impact

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

Photopatterned Membranes and Chemical Gradients Enable Scalable Phenotypic Organization of Primary Human Colon Epithelial Models

2019 ◽  
Author(s):  
Sam Hinman ◽  
Yuli Wang ◽  
Nancy Allbritton
Keyword(s):  
Human Colon ◽  
Cell Types ◽  
Self Renewal ◽  
Chemical Gradients ◽  
Plate Spacing ◽  
Wide Range ◽  
Cell Compartmentalization ◽  
The Impact

Biochemical gradients across the intestinal epithelium play a major role in governing intestinal stem cell compartmentalization, differentiation dynamics, and organ-level self-renewal. Advances in primary cell-derived <i>in vitro</i> models, in which a full suite of stem and differentiated cell types are present, have vastly accelerated our understanding of intestinal homeostasis and disease. However, scalable platforms that recapitulate the architecture and gradients present <i>in vivo</i> are absent. We present a platform in which individually addressable arrays of chemical gradients along the crypt long axis can be generated, enabling scalable culture of <i>in vitro</i> colonic epithelial replicas. The platform utilizes standardized well plate spacing, maintains access to basal and luminal compartments, and relies on a photopatterned porous membrane to act as diffusion windows while supporting the<i> in vitro </i>crypts. Simultaneous fabrication of 3,875 crypts over a single membrane was developed. Growth factor gradients were modelled and then experimentally optimized to promote long-term health and self-renewal of the crypts which were assayed <i>in situ</i> by confocal fluorescence microscopy. The cultured <i>in vitro</i> crypt arrays successfully recapitulated the architecture, stem/proliferative and differentiated cell compartmentalization, and luminal-to-basal polarity observed <i>in vivo</i>. Furthermore, known signaling regulators produced measurable and predictable effects on the proliferative and differentiated cell compartments. This platform is readily adaptable to the screening of tissue from individual patients to assay the impact of food and bacterial metabolites and/or drugs on colonic crypt dynamics. Importantly, the cassette is compatible with a wide range of sensing/detection modalities, and the developed fabrication methods should find applications for other cell and tissue types.

scholarly journals Mesenchymal Stromal Cell-Derived Extracellular Vesicles – Silver Linings for Cartilage Regeneration?

2020 ◽  
Vol 8 ◽  
Author(s):  
Andrea De Luna ◽  
Alexander Otahal ◽  
Stefan Nehrer
Keyword(s):  
Extracellular Vesicles ◽  
Treatment Options ◽  
Cartilage Regeneration ◽  
Bioactive Molecules ◽  
Paracrine Factors ◽  
Differentiation Potential ◽  
Vast Number ◽  
The Impact

As the world’s population is aging, the incidence of the degenerative disease Osteoarthritis (OA) is increasing. Current treatment options of OA focus on the alleviation of the symptoms including pain and inflammation rather than on restoration of the articular cartilage. Cell-based therapies including the application of mesenchymal stromal cells (MSCs) have been a promising tool for cartilage regeneration approaches. Due to their immunomodulatory properties, their differentiation potential into cells of the mesodermal lineage as well as the plurality of sources from which they can be isolated, MSCs have been applied in a vast number of studies focusing on the establishment of new treatment options for Osteoarthritis. Despite promising outcomes in vitro and in vivo, applications of MSCs are connected with teratoma formation, limited lifespan of differentiated cells as well as rejection of the cells after transplantation, highlighting the need for new cell free approaches harboring the beneficial properties of MSCs. It has been demonstrated that the regenerative potential of MSCs is mediated by the release of paracrine factors rather than by differentiation into cells of the desired tissue. Besides soluble factors, extracellular vesicles are the major component of a cell’s secretome. They represent novel mechanisms by which (pathogenic) signals can be communicated between cell types as they deliver bioactive molecules (nucleic acids, proteins, lipids) from the cell of origin to the target cell leading to specific biological processes upon uptake. This review will give an overview about extracellular vesicles including general characteristics, isolation methods and characterization approaches. Furthermore, the role of MSC-derived extracellular vesicles in in vitro and in vivo studies for cartilage regeneration will be summarized with special focus on transported miRNA which either favored the progression of OA or protected the cartilage from degradation. In addition, studies will be reviewed investigating the impact of MSC-derived extracellular vesicles on inflammatory arthritis. As extracellular vesicles are present in all body fluids, their application as potential biomarkers for OA will also be discussed in this review. Finally, studies exploring the combination of MSC-derived extracellular vesicles with biomaterials for tissue engineering approaches are summarized.

scholarly journals Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1596
Author(s):  
David R. Brigstock
Keyword(s):  
Extracellular Vesicles ◽  
Cell Types ◽  
Chronic Injury ◽  
Increased Risk ◽  
End Stage ◽  
Parenchymal Cells ◽  
Risk Of Cancer ◽  
Organ Fibrosis

Fibrosis is the unrelenting deposition of excessively large amounts of insoluble interstitial collagen due to profound matrigenic activities of wound-associated myofibroblasts during chronic injury in diverse tissues and organs. It is a highly debilitating pathology that affects millions of people globally and leads to decreased function of vital organs and increased risk of cancer and end-stage organ disease. Extracellular vesicles (EVs) produced within the chronic wound environment have emerged as important vehicles for conveying pro-fibrotic signals between many of the cell types involved in driving the fibrotic response. On the other hand, EVs from sources such as stem cells, uninjured parenchymal cells, and circulation have in vitro and in vivo anti-fibrotic activities that have provided novel and much-needed therapeutic options. Finally, EVs in body fluids of fibrotic individuals contain cargo components that may have utility as fibrosis biomarkers, which could circumvent current obstacles to fibrosis measurement in the clinic, allowing fibrosis stage, progression, or regression to be determined in a manner that is accurate, safe, minimally-invasive, and conducive to repetitive testing. This review highlights the rapid and recent progress in our understanding of EV-mediated fibrotic pathogenesis, anti-fibrotic therapy, and fibrosis staging in the lung, kidney, heart, liver, pancreas, and skin.

scholarly journals Tumor-Derived miR-378a-3p-Containing Extracellular Vesicles Promote Osteolysis by Activating a Dyrk1a/Nfatc1/Angptl2 Axis for Bone Metastasis

2021 ◽  
Author(s):  
Jialin Wang ◽  
Xinxing Du ◽  
Xiao Wang ◽  
Huixiang Xiao ◽  
Nan Jing ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Extracellular Vesicles ◽  
Nuclear Translocation ◽  
Intracellular Concentration ◽  
Luciferase Reporter ◽  
Metastatic Niche ◽  
Mesenchymal Transition

Abstract Background The majority of the deaths of prostate cancer (PCa) are caused by progression to bone metastatic PCa. The importance of extracellular vesicles (EVs) in the formation of the pre-metastatic niche has been demonstrated in recent years. However, whether and how tumor-derived EVs interact with bone marrow macrophages (BMMs) to release EV-delivered microRNAs to promote osteolysis and to activate pre-metastatic niche formation for PCa bone metastasis remain unclear. Methods Bioinformatics and qRT-PCR analyses were used to screen microRNAs and to identify the elevated expression of miR-378a-3p in both serum-derived EVs from PCa patients and in culture medium-derived EVs from PCa cell lines. Functional assays in vitro and in vivo were performed to investigate the functions of miR-378a-3p during PCa progression. IF staining and Dual-luciferase reporter, co-IP, western blot, RIP and ChIP assays were conducted to reveal the underlying mechanism. Results We found that EV-mediated release of miR-378a-3p from tumor cells was upregulated in bone-metastatic PCa which keeps a low intracellular concentration of miR-378a-3p, to promote proliferation and the MAOA-mediated epithelial-to-mesenchymal transition (EMT) in PCa cells. In addition, we demonstrated that the enrichment of miR-378a-3p in tumor derived EVs was induced by overexpression of hnRNPA2B1 as a transfer chaperone. After miR-378a-3p-enriched EVs were taken in by BMMs, elevated intracellular concentration of miR-378a-3p promoted osteolytic progression by targeting the Dyrk1a/Nfatc1 pathway. Mechanistically, inhibition of Dyrk1a by miR-378a-3p improved the nuclear translocation of Nfatc1 to promote expression of the downstream target gene Angptl2. As a feedback, increased secretion of Angptl2 into the tumor environment promoted PCa progression. Conclusions Our findings indicate that tumor-derived miR-378a-3p-containing EVs play a significant role in promoting prostate cancer bone metastasis by activating a Dyrk1a/Nfatc1/Angptl2 axis in BMMs to induce osteolytic progression, which implicates that miR-378a-3p may be a potential predictor of metastatic PCa. Moreover, reducing the release of miR-378a-3p-containing EVs or inhibiting the recruitment of miR-378a-3p into tumor-derived EVs might be a potential therapeutic strategy for PCa metastasis.

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