Genome-wide expression analysis of high-growth and low-growth capacity human mesenchymal stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135401 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:Human Mesenchymal stem cells (hMSCs) are multi-potential cells which are widely used in cell therapy. However, the frequently emerged senescence and decrease of differentiation capabilities limited the broad applications of MSC. In this study, hMSCs were treated by rapamycin, oltipraz, metformin, and vitamin C for the indicated time and the cells were subjected to senescence evaluation and trilineage differentiation. Transcriptomics dataset of hMSCs after drugs treatment was analyzed to interpret biological pathways responsible for the anti-senescence effects. Although four drugs exhibited significant activities in promoting MSC osteogenic differentiation, metformin is the optimal drug to promote trilineage differentiation. GO terms illustrated that the anti-aging effects of drugs were mainly associated with cellular senescence, mitotic and meiosis process. The method established and discussed in this study can be used to study different biological phenotypes upon drug intervention in MSC which will extend the clinical application of hMSCs.
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Project description:Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to 5 oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization and H-RASv12 mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches, and constitutes a proof-of-concept to employ hMSCs as target cell for modeling other fusion gene-associated human sarcomas. Wild type (MSC-0H) or transformed (MSC-5H) BM-hMSCs were transduced with concentrated viral particles expressing either pRRL-EF1?-PGK-GFP (empty vector; GFP) or pRRL-EF1?-FUS-CHOP-PGK-GFP (FUSCHOP expressing vector; FC) in order to generate MSC-0H-GFP, MSC-0H-FC, MSC-5H-GFP and MSC-5H-FC cell lines. MSC-0H-GFP and MSC-0H-FC cells did not develop tumors, meanwhile MSC-5H-GFP cells gave rise to undifferentiated sarcomas and MSC-5H-FC originated mixoid liposarcoma tumors when inoculated into immunedeficient mice. Several cell lines were derived from tumors developed from MSC-5H-GFP (T-5H-GFP-1 to -3 cell lines) and MSC-5H-FC (T-5H-FC-1 to -3 cell lines) cells. Gene expression analysis was performed using MSC-0H, MSC-5H and T-5H cell lines and lists of differentially expressed genes were created by comparing the gene expression profiles of MSC-0H-FC, MSC-5H-FC and T-5H-FC cell types to the control MSC-0H-GFP cells.
2013-06-18 | E-GEOD-48030 | biostudies-arrayexpress
Project description:Genome-wide expression analysis of high-growth and low-growth capacity human mesenchymal stem cells
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Project description:Human multipotent mesenchymal stem cells (MSCs), isolated based on their adherence to plastic, show poor growth and differentiation and frequently contain contaminating cells, which limits to clarify their own characteristics. In this study, the identification of two cell surface markers, LNGFR and Thy-1, allowed the prospective isolation of highly purified clonogenic human MSCs. Furthermore, single cell sorting assays followed by in vitro expansion revealed three distinct MSC subpopulations: rapidly-, moderately- and slowly proliferating MSC clones (RPCs, MPCs and SPCs, respectively). While RPCs exhibited robust multilineage differentiation and self-renewal potency, MPCs and SPCs contained a majority of senescent cells and exhibited frequent genome errors. Single cell sorting assays followed by in vitro expansion revealed three distinct MSC subpopulations: rapidly-, moderately- and slowly proliferating MSC clones (RPCs, MPCs and SPCs, respectively). Sample: RPC, MPC and SPC (n=3).
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Project description:Human mesenchymal stem cells (hMSC) have an extensive potential for clinical applications in cell therapy. However, very little is known of the specific molecular regulatory mechanisms that control the therapeutical properties of these cells. We aimed to identify microRNAs (miRNAs) that could be involved in controlling the transition between the self-renewing (undifferentiated) and the reparative (differentiated) phenotypes of hMSCs. MicroRNA microarrays were used to identify miRNAs that are upregulated in undifferentiated hMSCs. For that, we compared the miRNA expression profiles of undifferentiated bone marrow-derived hMSCs with the same primary cell lines after 9 days of in vitro adipogenic or osteogenic induction. We also compared the miRNA expression profiles of undifferentiated hMSCs with skin fibroblasts (a mesenchymal cell lineage with a more restricted differentiation potential). These experiments allowed us to identify miR-335 as the only miRNA downregulated upon MSC differentiation as well as in MSCs in comparison with skin fibroblasts. Gene expression microarrays were used to identify genes that are downregulated in hMSCs overexpressing miR-335. We compared the miRNA expression profiles of hMSCs transduced with a lentiviral vector encoding miR-335 with MSCs transduced with a control lentiviral vector. Our results suggest miR-335 downregulation could be one of the triggers for the initiation of MSCs activities involved in tissue repair and remodelling, including cell migration and differentiation. We compared the miRNA expression profiles of undifferentiated bone marrow-derived hMSCs with the same primary cell lines after 9 days of adipogenic or osteogenic induction, as well as with skin fibroblasts. A total of four independent samples were used for each condition. For the adipogenic/osteogenic vs. undifferentiated MSC comparison, the RNA samples were pooled (two independent samples/pool) before labeling. We also compared the miRNA expression profiles of hMSCs transduced with the lentiviral vector pLV-EmGFP-MIRN335 with MSCs transduced with the control vector pLV-EmGFP-Mock. For the gene expression microarrays, a total of three independent samples were used for each condition.
2010-05-06 | E-GEOD-19232 | biostudies-arrayexpress
Project description:Four human mesenchymal stem cells (hMSC) clones (MSC-1, MSC-2, MSC-3, MSC-4) and three different glioblastoma multiformae (GBM) cell lines (U87-MG, U251, U373) were used to study their mutual paracrine interactions in the indirect co-cultures compared to their monocultures, which were grown under the same experimental conditions. The effects on cell growth, proliferation and invasion in matrigel were quantified. Further on, bioinformatic tools were used to relate these results to the data obtained from cytokine macroarrays and DNA microarrays that revealed proteins and genes significantly involved in the interaction. We showed that hMSC are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, U87-MG cells even more strongly inversely affected some of these characteristics in hMSCs. We found several chemokines that may account for changed co-cultured cells’ phenotype, affecting genes associated with proliferation and senescence. CCL2/MCP-1 was collectively identified as the most significantly regulated chemokine during hMSC and U87-MG paracrine signalling. Its role in U87-MG cell invasion was also functionally confirmed. Microarray data deposited here contain gene expression data from three biological replicates of monocultures and indirect co-cultures of MSC-4 and U87-MG cells, representing 12 microarrays. Three biological replicates of four cell set-ups were performed: MSC-4 monoculture, U87-MG monoculture, MSC-4 co-cultured with U87-MG (in Boyden chambers) and U87-MG co-cultured with MSC-4 (in Boyden chambers).
2011-12-20 | E-GEOD-26283 | biostudies-arrayexpress
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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.
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Project description:Understanding the molecular regulation of adipogenesis in farm animals would bring benefits both to animal meat production and to the nascent field of cultivated meat, where adipose tissue provides enhanced flavour and texture profiles of biomanufactured meat products. Adipogenic progenitors are found within heterogenous mesenchymal stem cell (MSC) populations in fat and other animal tissues. Such populations contain only a fraction of bona-fide adipocyte progenitors, resulting in limited and variable fat-forming capacity that is highly dependent on animal of origin. The identification of novel markers of pre-adipocytes in species such as the pig would have significant potential towards increasing the efficiency and sustainability of both animal meat production and cultured fat manufacture. Thus, the aim of this study was to compare the transcriptional signatures of MSC clones with a high or low adipogenic capacity in pig.
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Project description:Four human mesenchymal stem cells (hMSC) clones (MSC-1, MSC-2, MSC-3, MSC-4) and three different glioblastoma multiformae (GBM) cell lines (U87-MG, U251, U373) were used to study their mutual paracrine interactions in the indirect co-cultures compared to their monocultures, which were grown under the same experimental conditions. The effects on cell growth, proliferation and invasion in matrigel were quantified. Further on, bioinformatic tools were used to relate these results to the data obtained from cytokine macroarrays and DNA microarrays that revealed proteins and genes significantly involved in the interaction. We showed that hMSC are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, U87-MG cells even more strongly inversely affected some of these characteristics in hMSCs. We found several chemokines that may account for changed co-cultured cells’ phenotype, affecting genes associated with proliferation and senescence. CCL2/MCP-1 was collectively identified as the most significantly regulated chemokine during hMSC and U87-MG paracrine signalling. Its role in U87-MG cell invasion was also functionally confirmed. Microarray data deposited here contain gene expression data from three biological replicates of monocultures and indirect co-cultures of MSC-4 and U87-MG cells, representing 12 microarrays.
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