Umbilical Mesenchymal Stem Cell-derived Exosomes Facilitate Spinal Cord Functional Recovery Through miR-199a-3p/145-5p mediated NGF/TrkA Signaling Pathway in Rats
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ABSTRACT:
PROVIDER: PRJNA670508 | ENA |
REPOSITORIES: ENA
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Project description:Background: Though exosomes, as the by-products of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), it remains unclear through which manner exosomes act. Aim: In order to figure out whether exosomes attenuate lesion size of SCI by the amelioration of neuronal injury triggered by secondary inflammatory storm and induction of inner motivation of neurite outgrowth, we designed and performed this experiment. Methods: We determined absolute contents of all exosomal miRNAs and investigated the potential mechanisms of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and vitro. Results: miR-199a-3p/145-5p, which were relatively top-ranking miRNAs in exosomes, promoted PC12 cells differentiation suppressed by lipopolysaccharide (LPS) in vitro through the modulation of NGF/TrkA pathway. We also demonstrated that Cblb was the direct target of miR-199a-3p and Cbl was the direct target of miR-145-5p. Cblb and Cbl genes knock down revealed that TrkA ubiquitylation level significantly decreased, subsequently, activating the NGF/TrkA downstream pathways Akt and Erk. In return, overexpression of Cblb and Cbl suggested that TrkA ubiquitylation level significantly increased, subsequently, inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and co-immunoprecipitation confirmed the direct interaction between TrkA and Cblb, TrkA and Cbl. In vivo experiment, exosomal miR-199a-3p/145-5p were found to up-regulate TrkA expression in the lesion site and promote locomotor function of SCI rats as well. Conclusion: In summary, our study suggested that hUC-MSCs derived exosomes may treat SCI by transferring miR-199a-3p/145-5p to neurons, and modulating TrkA ubiquitylation, and strengthening the NGF/TrkA signaling pathway in SCI rats.
2020-12-08 | GSE159814 | GEO
Project description: Not available
| S-EPMC7879635 | biostudies-literature
Project description:Pathological markers that can monitor the progression of gastric cancer (GC) may facilitate the diagnosis and treatment of patients with diffuse GC (DGC). To identify microRNAs (miRNAs) that can differentiate between early and advanced DGC in the gastric mucosa, miRNA expression profiling was performed using the NanoString nCounter method in human DGC tumors. Ectopic expression of miR-199a and miR-199b (miR-199a/b) in SNU601 human GC cells accelerated the growth rate, viability, and motility of cancer cells and increased the tumor volume and weight in a mouse xenograft model. To study their clinicopathological roles in patients with GC, miR-199a/b levels were measured in human GC tumor samples using in situ hybridization. High miR-199a/b expression level was associated with enhanced lymphovascular invasion, advanced T stage, and lymph-node metastasis. Using the 3′-untranslated region (UTR) luciferase assay, Frizzled-6 (FZD6) was confirmed to be a direct target of miR-199a/b in GC cells. siRNA-mediated depletion of FZD6 enhanced the motility of SNU601 cells, and addback of FZD6 restored cancer cell motility stimulated by miR-199a/b. In conclusion, miR-199a/b promotes DGC progression by targeting FZD6, implying that miR-199a/b can be used as prognostic and diagnostic biomarkers for the disease.
2023-10-26 | GSE227288 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress
Project description:Expression profiling of PC12 cells stably transfected with GFP, GFP-SH2-Bb, or GFP-SH2-Bb(R555E), treated with or without NGF for 6h Keywords: response to NGF
2007-03-27 | GSE4557 | GEO
Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.
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Project description:miR-199a expression was enforced in HMLE cells using lentiviral vector pLEX. The transcriptome profiles changes following miR-199a expression was studied.
2017-05-05 | GSE85629 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below.
2013-02-01 | GSE34818 | GEO
Project description:miR-145 is downregulated in multiple cancers. The introduction of miR-145 could alleviate the tumor burden in the pancreatic cancer mouse model. However, how miR-145 mediates the tumor suppression is still an open question. In this study, we aimed to identify the targets of miR-145 using a SILAC approach.
2014-10-28 | PXD001260 | Pride
Project description:We found that miR-199a-3p expression is decreased in cSCC biopsies and cell lines compared to normal skin biopsies or normal keratinocytes cell. To understand the role lost expression of miR-199a-3p might have in tumorigenesis of keratinocytes, we aimed to fine possible biochemical pathways and possible targets of miR-199a-3p in cSCC. In order do so, we overexpressed miR-199a-3p in cSCC and used microarrays to find global gene expression affected by miR-199a-3p.
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