Recurrent chromosomal abnormalities in human embryonic stem cells

Spits, Claudia; Mateizel, Ileana; Geens, Mieke; Mertzanidou, Afroditi; Staessen, Cathérine; Vandeskelde, Y; Elst, Josiane Van Der; Liebaers, Inge; Sermon, Karen

doi:10.1038/nbt.1510

Cited by 229 publications

(175 citation statements)

References 13 publications

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“…32 De-novo aberrations in hESC lines have been previously reported, some of them shows very fast culture take over. 33 Here, we report high prevalence of aneuploidy in chromosomes 17 and 18, and although it is not statistically significant higher than other chromosomes, trisomy 17 aneuploidy is highly interesting as it was rarely reported in iPSCs. Significant difference was found in our research between monosomy and trisomy rate, suggesting that chromosome loss is more common.…”

Section: Aneuploidy Screeningmentioning

confidence: 51%

Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q

et al. 2012

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Pluripotency and proliferative capacity of human embryonic stem cells (hESCs) make them a promising source for basic and applied research as well as in therapeutic medicine. The introduction of human induced pluripotent cells (hiPSCs) holds great promise for patient-tailored regenerative medicine therapies. However, for hESCs and hiPSCs to be applied for therapeutic purposes, long-term genomic stability in culture must be maintained. Until recently, G-banding analysis was considered as the default approach for detecting chromosomal abnormalities in stem cells. Our goal in this study was to apply fluorescence in-situ hybridization (FISH) and comparative genomic hybridization (CGH) for the screening of pluripotent stem cells, which will enable us identifying chromosomal abnormalities in stem cells genome with a better resolution. We studied three hESC lines and two hiPSC lines over long-term culture. Aneuploidy rates were evaluated at different passages, using FISH probes (12,13,16,17,18,21,X,Y). Genomic integrity was shown to be maintained at early passages of hESCs and hiPSCs but, at late passages, we observed low rates mosaiciam in hESCs, which implies a direct correlation between number of passages and increased aneuploidy rate. In addition, CGH analysis revealed a recurrent genomic instability, involving the gain of chromosome 1q. This finding was detected in two unrelated cell lines of different origin and implies that gains of chromosome 1q may endow a clonal advantage in culture. These findings, which could only partially be detected by conventional cytogenetic methods, emphasize the importance of using molecular cytogenetic methods for tracking genomic instability in stem cells.

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Section: Aneuploidy Screeningmentioning

confidence: 51%

Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q

et al. 2012

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“…All hESC lines were characterized using aCGH, initially using in-house arrays from the Nucleomics Core (VIB, K.U. Leuven) 20 and later using the 4 Â 44 K Human Genome array as described in the section below.…”

Section: Methodsmentioning

confidence: 99%

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations

et al. 2014

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Current knowledge on chromosomal mosaicism in human cell cultures is mostly based on cytogenetic banding methods. The recent development of high-resolution full-genome analysis methods applicable to single cells is providing new insights into genetic and cellular diversity. Here we study the genetic content of 92 individual human cells, including fibroblasts, amniocytes and embryonic stem cells (hESCs), using single-cell array-based comparative genomic hybridization (aCGH). We find that human somatic and embryonic stem cell cultures show significant fractions of cells carrying unique megabase-scale chromosomal abnormalities, forming genetic mosaics that could not have been detected by conventional cytogenetic methods. These findings are confirmed by studying seven clonal hESC sub-lines by aCGH. Furthermore, fluorescent in situ hybridisation reveals an increased instability of the subtelomeric regions in hESC as compared to somatic cells. This genetic heterogeneity may have an impact on experimental results and, in the case of hESC, on their potential clinical use.

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“…This might be particularly useful since S684 Review. Genetic evaluation of therapeutic hESC E. Stephenson et al hESCs in culture have been shown to acquire small chromosomal amplifications or deletions (Maitra et al 2005;Lefort et al 2008;Spits et al 2008;Hovatta et al 2010;Närvä et al 2010). UPD, a condition in which both alleles have originated from a single parent, occurs as heterodisomy and isodisomy (Engel 1980;Robinson 2000).…”

Section: Upd-a Form Of Lohmentioning

confidence: 99%

Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells

Stephenson

Ogilvie

Patel

et al. 2010

J. R. Soc. Interface.

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The use of stem cells for regenerative medicine has captured the imagination of the public, with media attention contributing to rising expectations of clinical benefits. Human embryonic stem cells (hESCs) are the best model for capital investment in stem cell therapy and there is a clear need for their robust genetic characterization before scaling-up cell expansion for that purpose. We have to be certain that the genome of the starting material is stable and normal, but the limited resolution of conventional karyotyping is unable to give us such assurance. Advanced molecular cytogenetic technologies such as array comparative genomic hybridization for identifying chromosomal imbalances, and single nucleotide polymorphism analysis for identifying ethnic background and loss of heterozygosity should be introduced as obligatory diagnostic tests for each newly derived hESC line before it is deposited in national stem cell banks. If this new quality standard becomes a requirement, as we are proposing here, it would facilitate and accelerate the banking process, since end-users would be able to select the most appropriate line for their particular application, thus improving efficiency and streamlining the route to manufacturing therapeutics. The pharmaceutical industry, which may use hESC-derived cells for drug screening, should not ignore their genomic profile as this may risk misinterpretation of results and significant waste of resources.

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Recurrent chromosomal abnormalities in human embryonic stem cells

Cited by 229 publications

References 13 publications

Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q

Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations

Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells

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