Ontology highlight
ABSTRACT:
PROVIDER: PRJNA592301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10549895.fastq.gz | Fastqsanger.gz |
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Project description:RNA-seq was performed on cultured human induced pluripotent cell derived cardiomyocytes (iPSC-CMs). There are four groups, with three samples per group: H1,H2,H3. Negative control. Healthy, normoxic iPSC-CMs D1,D2,D3. Positive control. iPSCs cultured under hypoxic (0-1% O2) for 48h with 2% v/v PBS as vehicle control EV1,EV2,EV3. Treatment 1. iPSCs cultured under hypoxic (0-1% O2) for 48h, with cardiac stromal cell derived extracellular vesicles, provided at a dose of 67ng/µl (2% v/v) EV21, EV23, EV24. Treatment 2 iPSCs cultured under hypoxic (0-1% O2) for 48h, with bone marrow mesenchymal stromal cell (BM-MSC) derived extracellular vesicles, provided at a dose of 67ng/µl (2% v/v) All EVs were isolated from cultured human cells using sequential centrifugation methods. Cells were cultured using commercial EV-depleted FBS to avoid contamination of bovine EVs. EVs were validated for CD81, CD9, ALIX positivity, and visualised by cryoEM. Particle to protein ratios were not different between cardiac and bone marrow EV isolates. Therefore EV doses were standardised so that the same dose by protein (67ng/µl) and EV number (~2,000 EVs per iPSC-CM) were added.
2024-10-02 | E-MTAB-13966 | biostudies-arrayexpress
Project description:Real-time quantitative PCR analysis of human mesenchymal stromal (MSC) cells extracellular vesicles (EV)
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Project description:Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication in autocrine or paracrine manner. We report that cancer-derived EV biomaterials reach nuclei of human melanoma and breast carcinoma cells and multipotent mesenchymal stromal cells (MSCs) through Rab7+ late endosome subdomains that penetrate into nuclear envelope invaginations. MSCs were exposed to cancer Evs in the presence or absence of drugs that block nucler import or export through the nuclear pores. Depletion of CD9 or inhibition of importin β1, two EV-associated molecules, abrogated the nuclear localization of EV-derived biomaterials and EV-induced early changes in MSC transcriptome notably in genes involved in inflammation. Also inhibition of nuclear export by leptomycin B inhibited early changes in MSC transcriptome. This novel cellular pathway may become a cancer therapeutic target.
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Project description:Phenotypic changes induced by extracellular vesicles (EVs) have been implicated in the recovery of acute kidney injury (AKI) induced by mesenchymal stromal cells (MSCs). miRNAs are potential candidates for cell reprogramming towards a pro-regenerative phenotype. The aim of the present study was to evaluate whether miRNA de-regulation inhibits the regenerative potential of MSCs and derived-EVs in a model of glycerol-induced AKI in SCID mice. For this purpose, we generated MSCs depleted of Drosha, a critical enzyme of miRNA maturation, to alter miRNA expression within MSCs and EVs. Drosha knock-down MSCs (MSC-Dsh) maintained the phenotype and differentiation capacity. They produced EVs that did not differ from those of wild type cells in quantity, surface molecule expression and internalization within renal tubular epithelial cells. However, EVs derived from MSC-Dsh (EV-Dsh) showed global down-regulation of miRNAs. Whereas, wild type MSCs and derived EVs were able to induce morphological and functional recovery in AKI, MSC-Dsh and EV-Dsh were ineffective. RNA sequencing analysis showed that genes deregulated in the kidney of AKI mice were restored by treatment with MSCs and EVs but not by MSC-Dsh and EV-Dsh. Gene Ontology analysis showed that down-regulated genes in AKI were associated with fatty acid metabolism. The up-regulated genes in AKI were involved in inflammation, ECM-receptor interaction and cell adhesion molecules. These alterations were reverted by treatment with wild type MSCs and EVs, but not by the Drosha counterparts. In conclusion, miRNA depletion in MSCs and EVs significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of miRNAs. RNA-seq
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Project description:Treatment of graft failure after allogeneic stem cell transplantation with mesenchymal stromal cells (MSC) is being evaluated clinically. MSC can exert their functions by the release of extracellular vesicles (EV). Our aim is to analyze changes induced in hematopoietic stem cells (HSC) after the incorporation of MSC-EV. MSC were isolated from healthy donors. MSC-EV were isolated by ultracentrifugation and characterized by flow cytometry (FC), Western-blot, electron microscopy and Nanosight. EV incorporation into HSC was analyzed by FC and confocal microscopy. To study HSC gene expression, RT-PCR and arrays were performed. Apoptosis and cell cycle were evaluated by FC and clonal growth by clonogenic assays in methylcellulose. The engraftment capacity of HSC was analyzed four weeks after transplantation in NOD-SCID mice. Our results showed that MSC-EV presented the characteristic morphology, size and inmunophenotype and were able to be incorporated into HSC. MSC-EV incorporation induced an a down-regulation of pro-apoptotic genes, an overexpression of genes involved in colony formation and cell proliferation together with an activation of the JAK-STAT pathway in HSC. A significant decrease in apoptosis (p=0.001), an increase of the percentage of cells in phase S and an increased CD44 expression (p=0.013) were confirmed by FC in HSC with MSC-EV. In addition, these HSC displayed a higher CFU-GM clonogenic potential (p=0.010). Finally, in the xenotransplantation model, the engraftment ability of human HSC with MSC-EV was significantly higher (p= 0.027). In summary, the incorporation of MSC-EV induces genomic and functional changes in HSC, increasing their clonogenic capacity and their engraftment ability.
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Project description:Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. Following successful treatment of an acute steroid-refractory Graft-versus-Host disease (GvHD) patient with EVs prepared from conditioned media of human bone marrow-derived MSCs, we focus on improving the MSC-EV production for the clinical application. Independent MSC-EV preparations all produced according to a standardized procedure, reveal broad immunomodulatory differences. Only a proportion of our MSC-EV products effectively modulate immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences, we have established an optimized mouse GvHD model. The functional testing of selected MSC-EV preparations demonstrate that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GvHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also fail to modulate GvHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, we failed to identify concrete proteins or miRNAs that could serve as surrogate markers. Thus, standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency prior to administration to patients. Here, we qualified the mdMLR assay for such analyses.
2023-06-12 | PXD032744 | Pride
Project description:Extracellular vesicles (EVs) of multipotent mesenchymal stromal cells (MSCs) in various studies have shown a wide range of cytoprotective effects, including neuroprotective ones. It is important to note that the therapeutic effect of EVs is observed regardless of the tissue from which MSCs were isolated. However, the mechanisms of the neuroprotective action of extracellular vesicles remain elusive. It is assumed that the proteins contained in EVs could make the main contribution to the therapeutic effects of EVs. The aim of this work was to study protein composition of EV obtained from MSCs in conjunction with the experiments on neuroprotective properties and mechanisms of the neuroprotective effects of EVs-MSC in in vitro and in vivo models of acute neurological diseases.
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Project description:Mesenchymal stromal cells (MSCs) are characterized by a regulatory phenotype and respond promptly to the environmental signals modulating their secretory activity. An appropriate preconditioning may induce MSCs to release secretomes with an enhanced regenerative potential. However, it fails to take into account that secretomes are composed by both soluble factors and extracellular vesicles (EVs), whose functions could be altered differently by the preconditioning approach. Here we demonstrate that the MSC secretome is strongly modulated by the simultaneous stimulation with hypoxia and pro-inflammatory cytokines, used to mimic the harsh environment present at the site of injury. The cargo content (in terms of miRNAs) of the corresponding EV fractions was less sensitive to the influence of the external stimuli.
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Project description:Primary epithelial cells isolated from fetal lungs of rat fetuses with or without lung hypoplasia induced by the administration of nitrofen to pregnant rats. Control group included epithelial cells from normal fetal lungs. Treatment with amniotic fluid stem cell derived extracellular vesicles or with mesenchymal stromal cell derived exosomes, RNA-seq of both cargos included.
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Project description:Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury (DILI) and acute liver failure (ALF), and patients with advanced APAP toxicity rarely benefit from N-acetylcysteine (NAC), which is the first-line agent used in the clinic. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have shown promising effects in the treatment of DILI by decreasing neutrophil infiltration. However, the specific mechanism underlying the therapeutic effects of MSCs or MSC-EVs still needs to be elucidated. In this study, by using RNA-seq, we found that CXCL1, which is a chemoattractant for neutrophils, is a key molecule in MSC-mediated amelioration of DILI, and by luciferase reporter assay, we verified that MSC-EV-derived miR-186-5p binds to the 3’-UTR of CXCL1 to inhibit its expression in hepatocytes. Neutralizing CXCL1 reduces APAP-induced liver damage in vivo, and the agomir miR-186-5p shows excellent potential in the treatment of DILI. Overall, these findings suggest that the use of MSC-EVs may be a promising novel strategy for preventing DILI and that targeting the miR-186-5P/CXCL1 axis is a feasible approach for improving the efficacy of MSCs in the treatment of DILI.
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