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Knockdown of miR-192 and miR-432 in progenitor cell-derived small extracellular vesicles enhances tissue repair in myocardial infarction

ABSTRACT: Small extracellular vesicles (sEVs) play a critical role in cardiac cell therapy by delivering molecular cargo and mediating cellular signaling. Among sEV cargo molecule types, microRNA (miRNA) is particularly potent and highly heterogenous. However, not all miRNAs in sEV are beneficial. Two previous studies utilizing computational modeling identified miR-192-5p and miR-432-5p as potentially deleterious in cardiac function and repair. Here, we show that knocking down miR-192-5p and miR-432-5p in cardiac c-kit+ cell-derived sEVs enhances the therapeutic capabilities of sEVs in vitro and in a rat in vivo model of cardiac ischemia reperfusion. miR-192-5p and miR-432-5p depleted CPC-sEVs enhance cardiac function by reducing fibrosis, enhancing mesenchymal stromal cell-like cell mobilization, and inducing macrophage polarization to the M2 phenotype. Knocking down deleterious miRNAs from sEV could be a promising therapeutic strategy for treatment of chronic myocardial infarction.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE196469 | GEO | 2022/12/31

REPOSITORIES: GEO

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Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.

Project description:Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. However, the altered secretome of senescent cells can promote the growth of the surrounding cancer cells. Although extracellular vesicles (EVs) have emerged as new players in intercellular communication, their role in the function of senescent cell secretome has been largely unexplored. Here, we show that exosome-like small EVs (sEVs) are important mediators of the pro-tumorigenic function of senescent cells. sEV-associated EphA2 secreted from senescent cells binds to ephrin-A1 that is highly expressed in several types of cancer cells and promotes cell proliferation through EphA2/ephrin-A1 reverse signalling. sEV sorting of EphA2 is increased in senescent cells due to its enhanced phosphorylation resulting from oxidative inactivation of PTP1B phosphatase. Our results demonstrate a novel mechanism of reactive oxygen species (ROS)-regulated cargo sorting into sEVs, which is critical for the potentially deleterious growth-promoting effect of the senescent cell secretome.

2017-02-28 | GSE81373 | GEO

Comparability of the small RNA secretome across human biofluids concomitantly collected from healthy adults

Project description:Small extracellular vesicles (sEV) are nano-sized (40-150 nm), membrane-encapsulated vesicles that are released by malignant or pathologic and non-pathologic cells into the extracellular space and function as intercellular signaling vectors through the horizontal transfer of biologic molecules, including microRNA (miRNA) and other small non-coding RNA (ncRNA), that can alter the phenotype of recipient cells. sEV are present in essentially all extracellular biofluids, including serum, urine and saliva, and offer a new avenue for discovery and development of novel biomarkers of various disease states and exposures. The objective of this study was to determine the similarities and differences between sEV ncRNA derived from saliva, serum and urine, as well as cell-free ncRNA from serum. Saliva, urine and serum were concomitantly collected from 4 healthy donors, and sEV were isolated from each respective biofluid, along with cfRNA from serum. sEVs were isolated from the respective biofluids via differential ultracentrifugation. Small RNA-sequencing was performed on each sample, and cluster analysis was performed based on ncRNA profiles. While some similarities existed in terms of sEV ncRNA cargo across biofluids, there are also notable differences in ncRNA class and ncRNA secretion, with each sEVs in each biofluid bearing a unique ncRNA profile. We conclude that sEV ncRNA cargo varies according to biofluid, so thus should be carefully selected and interpreted when designing translational or epidemiological studies.

2020-02-25 | GSE122621 | GEO

human embryo proteome reprogramming by endometrial extracellular vesicles

Project description:- Endometrial sEV protein cargo are hormonally regulated – EP treated sEVs are enriched in key players of embryo implantation - Endometrial sEVs are taken up by recipient trophectoderm cells - Endometrial EP-sEVs (or secretory phase sEVs) promote trophectoderm cell invasion via MAPK signalling pathway - Invasion-related proteins are enriched on Tsc cell surface following EP-sEV treatment

2021-11-17 | PXD027642 | Pride

Proteomic characterization of SEC-fractionated sEV subpopulations

Project description:The use of cardiac progenitor cell (CPC)-derived small extracellular vesicles (sEVs) has shown potential to stimulate cardiac repair. sEVs are released by cells and play a role in intercellular communication through transfer of their bioactive content. Increasing evidence indicates that sEVs present a heterogeneous population of vesicles. In the context of cardiac regeneration, studying sEV heterogeneity could provide new insights into mechanisms underlying sEV-mediated cardiac repair properties and help to improve the therapeutic application of CPC-derived sEVs. Here we used size-exclusion chromatography to isolate and fractionate EV subpopulations dervied from CPCs. We then applied a bottom-up proteomic approach to characterize the contents of individual EV subpopulations.

2024-01-26 | PXD032334 | Pride

Human Brain Small Extracellular Vesicles Contain Selectively-Packaged, Full-Length mRNA

Project description:Brain cells release and take up small extracellular vesicles (sEVs) containing bioactive nucleic acids. sEV exchange is hypothesized to contribute to stereotyped spread of neuropathological changes in the diseased brain. We assessed mRNA from sEVs of non-diseased (ND) and Alzheimer’s disease (AD) human postmortem brain, using short- and long-read sequencing. sEV transcriptomes were distinct from bulk tissue, showing enrichment for multiple genes including mRNAs encoding ribosomal proteins and L1Hs transposable elements. AD versus ND sEVs showed enrichment of inflammation-related and depletion of synaptic signaling mRNAs. sEV mRNA from cultured murine primary neurons, astrocytes, or microglia showed similarities with human brain sEVs and revealed cell-type specific packaging. Nearly 80% of human brain sEV transcripts sequenced using long-read sequencing were full-length. Motif analyses of sEV-enriched full-length isoforms revealed RNA-binding proteins that may be associated with sEV loading. Collectively, we show that mRNA in brain sEVs is selectively-packaged and altered by disease state.

2024-03-14 | GSE243611 | GEO

Human Brain Small Extracellular Vesicles Contain Selectively-Packaged, Full-Length mRNA [bulk Iso-Seq]

Project description:Brain cells release and take up small extracellular vesicles (sEVs) containing bioactive nucleic acids. sEV exchange is hypothesized to contribute to stereotyped spread of neuropathological changes in the diseased brain. We assessed mRNA from sEVs of non-diseased (ND) and Alzheimer’s disease (AD) human postmortem brains, using short- and long-read sequencing. sEV transcriptomes were distinct from bulk tissue, showing enrichment for multiple genes including mRNAs encoding ribosomal proteins and L1Hs transposable elements. AD versus ND sEVs showed enrichment of inflammation-related and depletion of synaptic signaling mRNAs. sEV mRNA from cultured murine primary neurons, astrocytes, or microglia showed similarities with human brain sEVs and revealed cell-type specific packaging. Nearly 80% of human brain sEV transcripts sequenced using long-read sequencing were full-length. Motif analyses of sEV-enriched full-length isoforms revealed RNA-binding proteins that may be associated with sEV loading. Collectively, we show that mRNA in brain sEVs is selectively-packaged and altered by disease state.

2024-03-14 | GSE255462 | GEO

Xeno-free cultured Mesenchymal Stromal Cells release Extracellular Vesicles with a “therapeutic” miRNA cargo ameliorating cartilage inflammation in vitro

Project description:Mesenchymal Stromal Cells (MSCs)-derived Extracellular Vesicles (EVs) emerged as an innovative strategy for the treatment of osteoarthritis (OA). Biological activity of EVs is generally driven by their cargo, which might be influenced by microenvironment. Therefore, pre-conditioning strategies, including modifications in culture conditions or oxygen tension could directly impact on MSCs paracrine activity. Methods: A xeno-free supplement (XFS) was used for isolation and expansion of MSCs and compared to conventional fetal bovine serum (FBS) culture. Bone Marrow-derived MSCs (BMSCs) were pre-conditioned under normoxia (20% O2) or under hypoxia (1% O2) and EVs production was evaluated. Anti-OA activity was evaluated by using an in vitro inflammatory model. miRNA content was also explored, to select putative miRNA that could be involved in a biological function. Results: Modulation of IL-6, IL-8 and COX-2 was evaluated on hACs simultaneously treated with IL-1α and BMSC-derived EVs. FBS-sEVs exerted a blunt inhibitory effect, while a strong anti-inflammatory outcome was achieved by XFS-sEVs. Interestingly, in both cases hypoxia pre-conditioning allowed to increase EVs effectiveness. Analysis of miRNA content showed the upregulation in XFS-hBMSC-derived EVs of miRNA known to have a chondroprotective role, such as let-7b-5p, miR-17, miR-145, miR-21-5p, miR-214-3p, miR-30b-5p, miR-30c-5p. Activated pathways and target genes were investigated in silico and most of the upregulated miRNAs were found to be involved in TGF-beta and Wnt signalling pathways, by targeting genes related to cartilage homeostasis. Conclusions: XFS medium was found to be suitable for isolation and expansion of MSCs, secreting EVs with a therapeutic cargo. The application of cells cultured exclusively in XFS overcomes issues of safety associated with serum-containing media and makes ready-to-use clinical therapies more accessible.

2023-02-28 | GSE209585 | GEO

MOLECULAR PROFILING OF DECOMPENSATED CIRRHOSIS BY A NOVEL microRNA SIGNATURE

Project description:Objectives Non-invasive staging of decompensated cirrhosis is an unmeet clinical need. The aims of this study were to characterize and validate a novel miRNA signature to stage decompensated cirrhosis and predict the portal pressure and cardiac dysfunction response to non-selective beta-blockers (NSBB). Design Serum samples from patients with decompensated cirrhosis (n=36) and healthy controls (n=36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes, and three miRNAs (miR-192-5p, miR-34a-5p and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, that was refractory in 18 (50%), and were placed on NSBB for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient (HVPG), and echocardiogram study was performed before and 1 month after NSBB. Results Cirrhotic patients had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p and miR-29a-5p (p<0.05). miR-452-5p and miR-429 expression were lower in NSBB responders (p=0.006). miR-181b-5p expression was greater in refractory- than in diuretic sensitive ascites (p=0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ=-0.46 p=0.007; and ρ=-0.41 p=0.01 respectively), and with diminished systolic contractility in patients with refractory ascites after NSBB (ρ=-0.55 p=0.02; and ρ=-0.55 p=0.02, respectively). Conclusion Analysis of a miRNA signature in serum distinguishes patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade, and those more likely to benefit from NSBB.

2021-02-10 | GSE150867 | GEO

Colorectal Cancer-derived Small Extracellular Vesicles Create an Inflammatory Pre-metastatic Niche through Macrophage Polarization in Liver Metastasis

Project description:Colon and liver have an inseparable relationship since embryological development. More than half of colorectal cancer patients developed liver metastases accompanied with poor prognosis. Recent evidence suggests that distant metastatic organs are “educated” by primary tumor-derived extracellular vesicles. Here we found that the liver-specific pro-metastatic effect of colorectal cancer (CRC)-derived small extracellular vesicles (sEVs). In vivo experiments showed that the injected fluorescence-labeled CRC-derived sEVs were accumulated and taken up by macrophages in the mouse liver. MicroRNA sequencing revealed the highest expression of microRNA (miR)-21-5p in CRC-derived sEVs. In vitro co-culture experiments showed that the sEVs polarized macrophages toward an interleukin-6(IL-6)-secreting type of macrophages. Further mouse experiments and microarray studies indicated that the CRC-sEVs increased macrophage invasion and induced an inflammatory microenvironment in the liver, which promoted liver metastasis of orthotropic- transplanted CRC cells. Most importantly, the TCGA data analysis and clinical sample examinations demonstrated that miR-21-5p expressions were sharply raised in the CRC tissues. We apply Tethered Cationic Lipoplex Nanoparticles (tCLN) technology in detecting CRC patients’ sEVs miR-21 in plasma and found strong correlation between sEVs-miR-21 and CRC liver metastasis. The serum IL-6 level was much higher in CRC patients with liver metastasis, and the liver metastasis relevance of MiR-21, macrophages, and IL-6 in CRC patients. Thus, we propose the role of CRC-derived sEVs in the formation of an inflammatory pre-metastatic niche in liver for CRC metastasis through macrophage polarization via a miR-21/TLRs pro-inflammation pathway.

2019-07-01 | GSE100435 | GEO

Characterization of microRNAs in spent culture medium associated with human embryo quality and development

Project description:Purpose: Given implantation failure limited the improvement of the in vitro fertilization (IVF) success rate, it was urgent to identify potential biomarkers for embryo quality and predicting the outcomes of IVF-ET. Methods: The expression profiles of 16 spent culture media (SCM) collected from embryos at the cleavage on Day 3 (D3 cleavage) and blastocyst stages on Day 5 (D5 blastocyst) during IVF cycles were determined with RNA-sequencing. Differentially expressed miRNAs (DEmiRNAs) were identified with p-value < 0.05 and |log2FC|> 1. Then, the miRNA-mRNA interaction networks were constructed by using Cytoscape software. Finally, the GO and KEGG pathway analysis of target genes of DEmiRNAs were conducted. Results: Compared with pregnant groups, 29 DEmiRNA were detected in non-pregnant groups at D3 cleavage, and 26 DEmiRNA were detected in non-pregnant group at D5 blastocyst. Among them, a total of six known miRNAs, including hsa-miR-199a-3p>hsa-miR-199b-3p, hsa-miR-199a-5p, hsa-miR-379-5p, hsa-miR-432-5p, hsa-miR-99a-5p and hsa-miR-483-5p, were identified. The results of GO and KEGG pathway analysis indicated that these target genes of DEmiRNAs were associated with various biological processes. Conclusion: In conclusion, we identified three miRNAs, including hsa-miR-199a-5p, hsa-miR-483-5p and hsa-miR-432-5p, may serve as biomarkers for embryo quality during IVF cycles.

2023-10-31 | GSE167961 | GEO

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