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Increased levels of aneuploidy and deregulation of ploidy controlling genes are associated with maintained cultures of hMSC

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Juan Estrada

PROVIDER: E-GEOD-39250 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Increased levels of aneuploidy and deregulation of ploidy controlling genes are associated with maintained cultures of hMSC

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.

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