Extracellular vesicles from human urine-derived stem cells prevent osteoporosis by transferring CTHRC1 and OPG.
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ABSTRACT:
SUBMITTER: Chen CY
PROVIDER: S-EPMC6594995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background-Osteoporosis is characterized by defects in both quality and quantity of bone tissue, which imply high susceptibility to fractures with limitations of autonomy. Current therapies for osteoporosis are mostly concentrated on how to inhibit bone resorption but give serious adverse effects. Therefore, more effective and safer therapies are needed that even encourage bone formation. Here we examined the effect of extracellular vesicles secreted by human amniotic fluid stem cells (AFSC) (AFSC-EV) on a model of osteoporosis in vitro. Methods-human AFSC-EV were added to the culture medium of a human pre-osteoblast cell line (HOB) induced to differentiate, and then treated with dexamethasone as osteoporosis inducer. Aspects of differentiation and viability were assessed by immunofluorescence, Western blot, mass spectrometry, and histological assays. Since steroids induce oxidative stress, the levels of reactive oxygen species and of redox related proteins were evaluated. Results-AFSC-EV were able to ameliorate the differentiation ability of HOB both in the case of pre-osteoblasts and when the differentiation process was affected by dexamethasone. Moreover, the viability was increased and parallelly apoptotic markers were reduced. The presence of EV positively modulated the redox unbalance due to dexamethasone. Conclusion-these findings demonstrated that EV from hAFSC have the ability to recover precursor cell potential and delay local bone loss in steroid-related osteoporosis.
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Project description:Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor model. Then, we observed that hUCMSC-derived extracellular vesicles (hUCMSC-EVs) contribute to the hUCMSC-promoted LUAD cell growth through a direct effect on LUAD cells. Furthermore, we showed that hUCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells, concomitant with reduced PTEN expression mediated by the hUCMSC-EV-transmitted miR-410. Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-miRNA and suggest that modification of hUCMSC-EVs might be an attractive therapeutic option for the clinical application of hUCMSC-EVs that would reduce unwanted side effects.
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Project description:With limited therapeutic intervention in preventing the progression to end-stage renal disease, chronic kidney disease (CKD) remains a global health-care burden. Aristolochic acid (AA) induced nephropathy is a model of CKD characterised by inflammation, tubular injury, and interstitial fibrosis. Human liver stem cell-derived extracellular vesicles (HLSC-EVs) have been reported to exhibit therapeutic properties in various disease models including acute kidney injury. In the present study, we aimed to investigate the effects of HLSC-EVs on tubular regeneration and interstitial fibrosis in an AA-induced mouse model of CKD. NSG mice were injected with HLSC-EVs 3?days after administering AA on a weekly basis for 4?weeks. Mice injected with AA significantly lost weight over the 4-week period. Deterioration in kidney function was also observed. Histology was performed to evaluate tubular necrosis, interstitial fibrosis, as well as infiltration of inflammatory cells/fibroblasts. Kidneys were also subjected to gene array analyses to evaluate regulation of microRNAs (miRNAs) and pro-fibrotic genes. The effect of HLSC-EVs was also tested in vitro to assess pro-fibrotic gene regulation in fibroblasts cocultured with AA pretreated tubular epithelial cells. Histological analyses showed that treatment with HLSC-EVs significantly reduced tubular necrosis, interstitial fibrosis, infiltration of CD45 cells and fibroblasts, which were all elevated during AA induced injury. At a molecular level, HLSC-EVs significantly inhibited the upregulation of the pro-fibrotic genes ?-Sma, Tgfb1, and Col1a1 in vivo and in vitro. Fibrosis gene array analyses revealed an upregulation of 35 pro-fibrotic genes in AA injured mice. Treatment with HLSC-EVs downregulated 14 pro-fibrotic genes in total, out of which, 5 were upregulated in mice injured with AA. Analyses of the total mouse miRnome identified several miRNAs involved in the regulation of fibrotic pathways, which were found to be modulated post-treatment with HLSC-EVs. These results indicate that HLSC-EVs play a regenerative role in CKD possibly through the regulation of genes and miRNAs that are activated during the progression of the disease.
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Project description:PurposeSeveral studies have found significant associations between asthma and microbiome. However, it is challenging to obtain-sputum and bronchoalveolar lavage samples from pediatric patients. Thus, we used voided urine to show that urine microbe-derived extracellular vesicles (EVs) in asthma are an available source for clinical research.MethodsFive urine samples were obtained at 2-3-month intervals from each patient with asthma (n = 20), and a single voided urine sample were obtained from each healthy child (n = 20). After isolating EVs, 16S rDNA pyrosequencing was performed. The Chao1 index and principal coordinate analysis (PCoA) were used to assess diversity. To predict microbiota functional capacities, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used based on the Kyoto Encyclopedia of Genes and Genomes pathway database. Eight covariates were included in the EnvFit analysis to identify significant factors in the asthma group.ResultsThe asthma group showed lower Chao1 bacterial richness, and PCoA-based clustering differed significantly. Two phyla, and 13 families and genera were enriched or depleted. Functional profiling revealed significant differences between the asthma and control groups. EnvFit analysis of correlation to age, sex, body mass index, infection, season, asthma phenotype, severity, and symptoms was not significant except for infections associated with visit 1 and the season of visit 2.ConclusionsThis study showed that microbe-derived EVs were constantly altered in the urine of children with asthma, consistent with the findings of previous studies indicating microbiome changes in the lung and gut. The urine may reflect the specific pattern of microbiome EVs in children with asthma.
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Project description:Osteoporosis is one of the most common skeletal disorders caused by the imbalance between bone formation and resorption, resulting in quantitative loss of bone tissue. Since stem cell-derived extracellular vesicles (EVs) are growing attention as novel cell-free therapeutics that have advantages over parental stem cells, the therapeutic effects of EVs from adipose tissue-derived stem cells (ASC-EVs) on osteoporosis pathogenesis were investigated. ASC-EVs were isolated by a multi-filtration system based on the tangential flow filtration (TFF) system and characterized using transmission electron microscopy, dynamic light scattering, zeta potential, flow cytometry, cytokine arrays, and enzyme-linked immunosorbent assay. EVs are rich in growth factors and cytokines related to bone metabolism and mesenchymal stem cell (MSC) migration. In particular, osteoprotegerin (OPG), a natural inhibitor of receptor activator of nuclear factor-κB ligand (RANKL), was highly enriched in ASC-EVs. We found that the intravenous administration of ASC-EVs attenuated bone loss in osteoporosis mice. Also, ASC-EVs significantly inhibited osteoclast differentiation of macrophages and promoted the migration of bone marrow-derived MSCs (BM-MSCs). However, OPG-depleted ASC-EVs did not show anti-osteoclastogenesis effects, demonstrating that OPG is critical for the therapeutic effects of ASC-EVs. Additionally, small RNA sequencing data were analysed to identify miRNA candidates related to anti-osteoporosis effects. miR-21-5p in ASC-EVs inhibited osteoclast differentiation through Acvr2a down-regulation. Also, let-7b-5p in ASC-EVs significantly reduced the expression of genes related to osteoclastogenesis. Finally, ASC-EVs reached the bone tissue after they were injected intravenously, and they remained longer. OPG, miR-21-5p, and let-7b-5p in ASC-EVs inhibit osteoclast differentiation and reduce gene expression related to bone resorption, suggesting that ASC-EVs are highly promising as cell-free therapeutic agents for osteoporosis treatment.
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Project description:Proteomic analysis of extracellular vesicles (EVs) from biological fluid is a powerful approach to discover potential biomarkers for human diseases including cancers, as EV secreted to biological fluids are originated from the affected tissue. In order to investigate significant molecules related to the pathogenesis of bladder cancer, EVs were isolated from patient urine which was analyzed by mass spectrometry based proteomics. Comparison of the EV proteome to the whole urine proteome demonstrated an increased number of protein identification in EV. Comparative MS analyses of urinary EV from control subjects and bladder cancer patients identified a total of 1,222 proteins. Statistical analyses provided 56 proteins significantly increased in bladder cancer urine, including proteins for which expression levels varied by cancer stage (P-value < 0.05). While urine represents a valuable, noninvasive specimen for biomarker discovery in urologic cancers, there is a high degree of intra- and inter-individual variability in urine samples. The enrichment of urinary EV demonstrated its capability and applicability of providing a focused identification of biologically relevant proteins in urological diseases.
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Project description:BackgroundExtracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) may play a vital role in a variety of biological processes, including cartilage regeneration. However, few studies reported their potential in the development of osteoarthritis (OA) previously. In this study, we explored the biological roles and underlying mechanism of MSCs-EVs in OA.ResultsCo-culture experiments revealed that MSCs-EVs could promote the expression of collagen type II alpha 1 chain (COL2A1), SRY-box transcription factor 9 (SOX9) and Aggrecan while negatively regulate the expression of chondrocyte hypertrophy markers matrix metallopeptidase 13 (MMP-13) and RUNX family transcription factor 2 (Runx2) in mouse chondrocytes in the OA model. Besides, the results of cell experiments indicated that MSCs-EVs could notably weaken the suppression of chondrocyte proliferation, migration and the promotion of chondrocyte apoptosis via interleukin1β (IL-1β) induction. In addition, MSCs-circHIPK3-EVs (EVs derived from MSCs overexpressing circHIPK3) considerably improved IL-1β-induced chondrocyte injury. Mechanistically, we elucidated that circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9.ConclusionThe findings in our study demonstrated that EVs-circHIPK3 participated in MSCs-EVs-mediated chondrocyte proliferation and migration induction and in chondrocyte apoptosis inhibition via the miR-124-3p/MYH9 axis. This offers a promising novel cell-free therapy for treating OA.
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