Exosomal miR-183-5p from human hepatocyte-derived liver progenitor-like cells promotes liver regeneration during acute liver failure
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ABSTRACT:
PROVIDER: PRJNA940991 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23700546.fastq.gz | Fastqsanger.gz | |||
| SRR23700547.fastq.gz | Fastqsanger.gz | |||
| SRR23700548.fastq.gz | Fastqsanger.gz | |||
| SRR23700549.fastq.gz | Fastqsanger.gz | |||
| SRR23700550.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocyte-derived liver progenitor-like cells (HepLPCs) can reversibly differentiate into mature hepatocytes and play important roles in liver regeneration following acute liver failure. However, the mechanisms by which HepLPCs exert these regulatory effects are unclear. Herein, we report that HepLPCs participate in reinitiating liver regeneration and improving survival during acute liver failure, at least in part, via miRNA-183-5p, which is released from HepLPCs in extracellular vesicles. Thus, these findings may identify novel targets and strategies for the treatment of acute liver failure.
2024-12-06 | GSE226645 | GEO
Project description:Overexpression of miR-183-5p|+2, but not of the other two isomiRs |0 and |+1, was observed to reduce cell cycle and cell proliferation in different triple-negative breast cancer cell lines. Therefore, we hypothesized that the |+2 isoform has targets distinct from the other two isoforms. To test this hypothesis, we overexpressed separately the three different isoforms or negative controls (siAllstar or mimic-Cltr) and performed Mass Spectrometry to identify differentially regulated proteins. Interestingly, a gene set enrichment analysis of the changes in protein expression revealed significant downregulation of transcriptional targets of E2F specifically in cells transfected with the |+2 isoform prompting us to validate the predicted isomiR specific target E2F1. Subsequently, we could show that direct targeting of E2F1 by miR-183-5p|+2 is responsible for the impact of the isomiR on cell cycle and proliferation.
2022-05-26 | PXD026763 | Pride
Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. To explore the functional relevance of miR-146a-5p up-regulation, we performed a genome-wide transcriptomic analysis of hepatocyte-like cells upon ectopic miR-146a-5p expression.
2016-05-09 | GSE79340 | GEO
Project description:The key exosomal miRNAs in adaptive response to drug-induced liver (DILI) and liver regeneration were investigated and proved. This study aimed to decipher the mechanism of restorative events in the adaptive response to DILI by investigating circulating exosomal miRNAs. Using toosendanin-induced liver injury model, exosomal miR-106b-5p was identified as a robust driver in the adaptive response of TILI.
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Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
2021-07-15 | GSE179961 | GEO
Project description:miR-182-5p Promotes Hepatocyte-Stellate Cell Crosstalk to Facilitate Liver Regeneration
| PRJNA850954 | ENA
Project description:A unique feature of the liver is its high regenerative capacity, which is essential to maintain liver homeostasis. However, key regulators of liver regeneration (LR) remain ill-defined. Here, we identify hepatic miR-182-5p as a key regulator of LR. Suppressing miR-182-5p, whose expression is significantly induced in the liver of mice post two-thirds partial hepatectomy (PH), abrogates PH-induced LR in mice. In contrast, liver-specific overexpression of miR-182-5p promotes LR in mice with PH. Overexpression of miR-182-5p failed to promote proliferation in hepatocytes, but stimulates proliferation when hepatocytes are cocultured with stellate cells. Mechanistically, miR-182-5p stimulates Cyp7a1-mediated cholic acid production in hepatocytes, which promotes hedgehog (Hh) ligand production in stellate cells, leading to the activation of Hh signaling in hepatocytes and consequent cell proliferation. Collectively, our study identified miR-182-5p as a critical regulator of LR and uncovers a Cyp7a1/cholic acid-dependent mechanism by which hepatocytes crosstalk to stellate cells to facilitate LR.
2022-08-10 | GSE206451 | GEO
Project description:Despite clear evidence that exosomal microRNAs (miRNAs) are able to modulate the cellular microenvironment and that exosomal RNA cargo selection is often deregulated in pathological conditions, the mechanisms controlling specific RNA sorting into extracellular vescicles are still poorly understood. We identified here the RNA binding protein SYNCRIP (Synaptotagmin-binding Cytoplasmic RNA-Interacting Protein, also known as hnRNP-Q or NSAP1) as a component of the hepatocyte exosomal miRNA sorting machinery. SYNCRIP was found to bind directly a subset of miRNAs enriched in exosomes, sharing a common extra-seed sequence that we named hEXO motif. In vivo knock-down of SYNCRIP impaired microRNA sorting in exosomes and the hEXO motif was proven to play a role in the regulation of miRNA localization, as its embedment into a poorly exported miRNA enhanced its loading into exosomes. These results provide a new insight in the mechanisms of miRNA exosomal sorting process, that ca be exploited to further understand the role of these extracellular vescicles in cell-to-cell communications and the control of tissue micoenvironments.
2016-09-02 | E-MTAB-4502 | biostudies-arrayexpress
Project description:Idiosyncratic drug-induced liver injury (DILI) is a rare, often difficult to predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune-mediated and may involve the activation of drug-specific T-cells. Exosomes are cell-derived vesicles that carry RNA, lipids and protein cargo from their cell of origin to distant cells, and may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid and nitroso-sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50-100 nm and expressed CD63. LC-MS/MS identified an average of 1200 proteins across all exosome samples. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso-sulfamethoxazole-treated hepatocytes selectively packaged a specific subset of proteins. LC-MS also revealed the presence of hepatocyte-derived exosomal proteins covalently modified with amoxicillin, flucloxacillin and nitroso-sulfamethoxazole. Uptake of exosomes by monocyte-derived dendritic cells occurred mainly via phagocytosis, and was inhibited by latrunculin A. This study reveals that exosomes have the potential to transmit drug-specific hepatocyte-derived signals to the immune system and provides a pathway for the induction of drug hapten-specific T-cell responses.
2019-05-14 | PXD010760 | Pride
Project description:The mechanisms underlying the effects of cancer-associated fibroblasts (CAFs) on cancer stemness and tumor progression in renal cell carcinoma (RCC) have not been elucidated yet. In the present study, we found that the enrichment of CAFs was positively associated with tumor progression and cancer stemness in RCC. Further investigation revealed that CAFs could enhance cancer stemness through delivering exosomes to RCC cells, and miR-181d-5p was identified as the critical exosomal miRNA in CAF secreted exosomes by small RNA sequencing and subsequent screening assays. Mechanistically, exosomal miR-181d-5p transferred from CAFs to RCC cells directly suppressed the expression of ring finger protein 43 (RNF43) and activated Wnt/β-catenin signaling pathway, thus promoted cancer stemness and tumor progression. Overexpression of RNF43 strongly suppressed stemness properties and the effects could be reverted by miR-181d-5p. Overall, our findings revealed a crucial mechanism by which CAFs secreted exosomal miRNAs to enhance cancer stemness and thus promote RCC progression, suggesting a new avenue based on CAF secreted miRNAs for more effective targeted therapies.
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