Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7586
Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy
Estrada, Juan C CNIC | Torres, Yaima CNIC | Benguria, Alberto CNIC | Dopazo, Ana CNIC | Roche, E | Carrera-Quintanar, L | Pérez, R A | Enriquez, Jose Antonio CNIC | Torres Ruiz, Raul CNIC | Ramirez, Juan Carlos CNIC | Samper, Enrique CNIC | Bernad, Antonio CNIC
Cell Death Dis. 2013; 4:e691
In most clinical trials, human mesenchymal stem cells (hMSCs) are expanded in vitro before implantation. The genetic stability of human stem cells is critical for their clinical use. However, the relationship between stem-cell expansion and genetic stability is poorly understood. Here, we demonstrate that within the normal expansion period, hMSC cultures show a high percentage of aneuploid cells that progressively increases until senescence. Despite this accumulation, we show that in a heterogeneous culture the senescence-prone hMSC subpopulation has a lower proliferation potential and a higher incidence of aneuploidy than the non-senescent subpopulation. We further show that senescence is linked to a novel transcriptional signature that includes a set of genes implicated in ploidy control. Overexpression of the telomerase catalytic subunit (human telomerase reverse transcriptase, hTERT) inhibited senescence, markedly reducing the levels of aneuploidy and preventing the dysregulation of ploidy-controlling genes. hMSC-replicative senescence was accompanied by an increase in oxygen consumption rate (OCR) and oxidative stress, but in long-term cultures that overexpress hTERT, these parameters were maintained at basal levels, comparable to unmodified hMSCs at initial passages. We therefore propose that hTERT contributes to genetic stability through its classical telomere maintenance function and also by reducing the levels of oxidative stress, possibly, by controlling mitochondrial physiology. Finally, we propose that aneuploidy is a relevant factor in the induction of senescence and should be assessed in hMSCs before their clinical use.
Cell Cycle Proteins | Cell Proliferation | Cells, Cultured | Chemokine CXCL12 | Gelsolin | Gene Expression | Gene Expression Regulation | Genomic Instability | Humans | Mesenchymal Stem Cells | Oxygen Consumption | Reactive Oxygen Species | Telomerase | Telomere Homeostasis | Aneuploidy | Cellular Senescence | Oxidative Stress
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