Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA170343 | ENA |
REPOSITORIES: ENA
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Project description:Human mesenchymal stem cells (hMSC) are being successfully evaluated for the treatment of a wide range of pathological conditions, including graft versus host disease (GVHD), bone and cartilage degeneration, complex fistula and myocardial infarction. Many of these clinical trials use hMSC, which have been previously expanded in vitro for 8-12 weeks under pro-oxidative “standard” cell culture conditions. These conditions could have negative effects over genetic stability and promote mutations and chromosomal abnormalities. Our FISH (Fluorescence in situ hybridization) analysis shows that aneuploidy is not unusual phenomenon in conventional cultures of hMSC and that it progressively increases with the passages. We further demonstrate that senescence is linked to transcriptional deregulation of a set of genes that have been previously implicated in cancer and ploidy control. Overexpression of hTERT reversed the deregulation of these ploidy control genes and maintained the basal levels of ploidy even during long-term culture, through its canonical function of telomere elongation and by reducing the levels of oxidative stress. We propose that the high levels of aneuploidy and deregulation of these genes would be relevant biomarkers of senescence in standard cultures of hMSC.
2012-10-30 | GSE39250 | GEO
Project description:Human mesenchymal stem cells (hMSC) are being successfully evaluated for the treatment of a wide range of pathological conditions, including graft versus host disease (GVHD), bone and cartilage degeneration, complex fistula and myocardial infarction. Many of these clinical trials use hMSC, which have been previously expanded in vitro for 8-12 weeks under pro-oxidative M-bM-^@M-^\standardM-bM-^@M-^] cell culture conditions. These conditions could have negative effects over genetic stability and promote mutations and chromosomal abnormalities. Our FISH (Fluorescence in situ hybridization) analysis shows that aneuploidy is not unusual phenomenon in conventional cultures of hMSC and that it progressively increases with the passages. We further demonstrate that senescence is linked to transcriptional deregulation of a set of genes that have been previously implicated in cancer and ploidy control. Overexpression of hTERT reversed the deregulation of these ploidy control genes and maintained the basal levels of ploidy even during long-term culture, through its canonical function of telomere elongation and by reducing the levels of oxidative stress. We propose that the high levels of aneuploidy and deregulation of these genes would be relevant biomarkers of senescence in standard cultures of hMSC. We compared the RNA expression profiles of adipose tissue-derived human mesenchymal stem cells cultured in standard cell culture condition at passages 2 with the same primary cell lines cultured by 21 passages. A total of four independent samples were used.
2012-10-30 | E-GEOD-39250 | biostudies-arrayexpress
Project description:Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms.
2014-08-14 | PXD001019 | Pride
Project description:Alteration of normal ploidy (aneuploidy) is an important mechanism of evolution of species. It has been linked to a rapid response to stress and is regarded as a hallmark of cancer. While increased genomic instability of aneuploid cells can accelerate genetic diversification and facilitate adaptation, these cells also face the adverse effects of gene imbalance, resulting in fitness cost. Here, to understand the mechanisms through which cells respond to aneuploidy and develop tolerance leading to fitness restoration, we subjected disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution, forcing disomy maintenance with selection markers. We characterized mutations, karyotype alterations and gene expression changes throughout adaptive evolution, and analyzed them to dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates, and endured a diverse array of adaptive events. Despite remarkable diversity of these events, cells tended to evolve towards normal ploidy through both chromosomal DNA loss and changes in gene expression. We identified genes commonly altered during the evolution of disomic strains, and genes recurrently mutated in multiple lines. Our analyses revealed protein translation, amino acid biosynthesis, transcription regulation, stress response, and nucleotide and protein degradation as key pathways for the adaptive response to aneuploidy and identified transcription factors that mediate this response. Together, these findings define cellular strategies that underlie tolerance to aneuploidy.
2018-08-31 | GSE119272 | GEO
Project description:Epithelial cancers are defined by a tumor-specific distribution of chromosomal aneuploidies that are maintained when cells metastasize and are conserved in cell lines derived from primary tumors. Correlations between genomic copy number and gene expression have been observed for different tumors including, colorectal (CRC), breast and pancreatic cancer. These ploidy-driven transcriptional deregulations are characterized by low-level expression changes of most genes on the affected chromosomes. The emergence of these aberrations at an early stage of tumorigenesis and the strong selection for the maintenance of these aneuploidies suggests that aneuploidy-dependent transcriptional deregulations might contribute to cellular transformation and maintenance of the malignant phenotype. The histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) has anticancer effects and is well known to lead to large scale gene expression changes. Here we assessed if TSA could disrupt the aneuploidy-driven gene expression in the aneuploid colon cancer cell line SW480 and the artificially generated aneuploid cell line DLD-1+7. We found that TSA increases transcriptional activity throughout the genome, yet inhibits aneuploidy-induced gene expression changes on chromosome 7. Among the TSA affected genes on chromosome 7 we identified potential CRC oncogenes. These experiments represent the first attempt to explain how histone acetylation affects aneuploidy-driven gene expression changes.
2017-10-01 | GSE100705 | GEO
Project description:Human mesenchymal stem cells (hMSC) play an important role in the maintenance of bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSC lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Here we show that targeting prion protein (PrP) by chemical intervention delays this process. When PrP expression was knocked down, cultures showed significant reduction in proliferation and differentiation capacity. In contrast hMSC expanded in the presence of small molecule modulator of PrP expression, 3/689, showed extended lifespan up to 10 population doublings. Upon re-plating cultures contained more than double the number of clonogenic progenitors and showed a 10 fold increase in engraftment levels in bone marrow 5 weeks post-transplant. Human MSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression. Gene expression profiling revealed upregulation of superoxide dismutase 2 in cells treated with 3/689, dependent on PrP expression, and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target to delay loss of proliferation and differentiation of hMSC with expansion in culture.
2012-01-30 | GSE31205 | GEO
Project description:Human mesenchymal stem cells (hMSC) play an important role in the maintenance of bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSC lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Here we show that targeting prion protein (PrP) by chemical intervention delays this process. When PrP expression was knocked down, cultures showed significant reduction in proliferation and differentiation capacity. In contrast hMSC expanded in the presence of small molecule modulator of PrP expression, 3/689, showed extended lifespan up to 10 population doublings. Upon re-plating cultures contained more than double the number of clonogenic progenitors and showed a 10 fold increase in engraftment levels in bone marrow 5 weeks post-transplant. Human MSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression. Gene expression profiling revealed upregulation of superoxide dismutase 2 in cells treated with 3/689, dependent on PrP expression, and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target to delay loss of proliferation and differentiation of hMSC with expansion in culture. Gene expression changes in hMSC expanded in the presence of 10uM small molecule modulator of prion protein 3/689 or DMSO were analysed at passage 2 and passage 8 from 3 separate donors.
2012-01-30 | E-GEOD-31205 | biostudies-arrayexpress
Project description:Genomic imbalance caused by varying the dosage of individual chromosomes or chromosomal segments (aneuploidy) has more detrimental effects than altering the dosage of complete chromosome sets (ploidy). Previous analysis on RNA-sequencing data of varied dosage of various chromosomal regions in maize (Zea mays) revealed global modulation of gene expression both on the varied chromosome (cis) and the remainder of the genome (trans). Dysregulation of microRNA (miRNA) dosage has been reported to have profound deleterious effects in many species. miRNAs are preferentially retained as duplicates following whole-genome duplication in grass species and are postulated to be dosage-sensitive. However, little is known regarding the role of miRNAs under genomic imbalance. We examined the impact of increased and/or decreased dosage of 1 interstitial and 19 distal chromosomal regions in concert with a whole-genome ploidy series of haploid, diploid, triploid, and tetraploid via small RNA-sequencing of diploid and haploid maize mature leaf tissue to investigate the impact of aneuploidy and polyploidy on expression of miRNAs. In general, cis miRNAs in aneuploids present a predominant gene-dosage effect, whereas trans miRNAs trend toward the inverse level, although other types of responses including dosage compensation, increased effect, and decreased effect also occur. Significant correlations between expression levels of miRNAs and their targets were identified in aneuploids, indicating the regulatory role of miRNAs on gene expression triggered by genomic imbalance. The findings provide novel insights into understanding of gene balance from the aspect of the function of miRNAs.
2022-05-12 | GSE189317 | GEO
Project description:Whereas most eukaryotic cells are diploid, carrying two chromosome sets, variances in ploidy are common. Despite the relative prevalence of ploidy changes and their relevance for pathology and evolution, the consequences of altered ploidy for cellular gene expression remain poorly understood. We quantified changes in the transcriptome and proteome of the yeast Saccharomyces cerevisiae with different ploidy, from the haploid to the tetraploid state. We found that the abundance of proteins increases with ploidy, but does not scale proportionally with increasing DNA content, suggesting a compensatory, cellular response to increases in ploidy. We further found that pathways related to cytoplasmic ribosomes and translation are differentially regulated. With increasing ploidy the cells reduced the rRNA and ribosomal protein abundance, although they maintained a constant translational output. These adaptations stem from an active process that involves the kinases Tor1 and Sch9 and the transcriptional corepressor of rDNA transcription, Tup1. Consistent with our results in yeast, human tetraploid cells show reduced mTORC1 activity and downregulated their ribosome content via the Tup1 homolog Tle1, demonstrating that the proteome remodeling pathway discovered here constitutes a conserved response pathway to increased ploidy.
2022-08-15 | GSE162513 | GEO
Project description:We aimed in this study to identify the differentially regulated genes by Dlk1 in hMSC cells using microarray technology in order to gain a better understanding of Dlk1-mediated signaling pathways during hMSC differentiation. Both control (hMSC-TERT)(not expressing Dlk1) and Dlk1 overexpressing cells (hMSC-Dlk1) were cultured in triplicate at 3×104 cells/cm2 in Petri-dish in standard growth medium. At 90-100% confluence, highly purified total cellular RNA was isolated from each of three independent cultures per cell line using RNeasy Kit (QIAGEN Nordic, West Sussex, UK) according to the manufacturer?s instructions
2006-02-10 | E-MEXP-560 | biostudies-arrayexpress