Abstract
The first Swiss human embryonic stem cell (hESC) line, CH-ES1, has shown features of a malignant cell line. It originated from the only single blastomere that survived cryopreservation of an embryo, and it more closely resembles teratocarcinoma lines than other hESC lines with respect to its abnormal karyotype and its formation of invasive tumors when injected into SCID mice. The aim of this study was to characterize the molecular basis of the oncogenicity of CH-ES1 cells, we looked for abnormal chromosomal copy number (by array Comparative Genomic Hybridization, aCGH) and single nucleotide polymorphisms (SNPs). To see how unique these changes were, we compared these results to data collected from the 2102Ep teratocarcinoma line and four hESC lines (H1, HS293, HS401 and SIVF-02) which displayed normal G-banding result. We identified genomic gains and losses in CH-ES1, including gains in areas containing several oncogenes. These features are similar to those observed in teratocarcinomas, and this explains the high malignancy. The CH-ES1 line was trisomic for chromosomes 1, 9, 12, 17, 19, 20 and X. Also the karyotypically (based on G-banding) normal hESC lines were also found to have several genomic changes that involved genes with known roles in cancer. The largest changes were found in the H1 line at passage number 56, when large 5 Mb duplications in chromosomes 1q32.2 and 22q12.2 were detected, but the losses and gains were seen already at passage 22. These changes found in the other lines highlight the importance of assessing the acquisition of genetic changes by hESCs before their use in regenerative medicine applications. They also point to the possibility that the acquisition of genetic changes by ESCs in culture may be used to explore certain aspects of the mechanisms regulating oncogenesis.
Highlights
Human embryonic stem cells and human embryonal carcinoma cells are two pluripotent cell types that share many characteristics [1] Human ECs are the malignant stem cells of teratocarcinomas, which are malignant tumors that have embryonal carcinoma components, and some may form teratocarcinomas when re-transplanted into an animal [2]
In addition to finding extensive genomic abnormalities in the CHES1 line, we found that the H1, HS293, HS401 and SIVF-02 lines share the general characteristics of human embryonic stem cell (hESC) that have been described by the International Stem Cell Initiative (ISCI) 1 [12]
Spontaneous teratocarcinomas generally arise from primordial germ cells, typically in the testis, and occasionally in the ovary or at non-gonad sites
Summary
Human embryonic stem cells (hESCs) and human embryonal carcinoma cells (hECs) are two pluripotent cell types that share many characteristics [1] Human ECs are the malignant stem cells of teratocarcinomas, which are malignant tumors that have embryonal carcinoma components, and some may form teratocarcinomas when re-transplanted into an animal [2]. Klimanskaya et al derived hESC lines from single isolated blastomeres at first by co-culture with other hESCs [9] but they were subsequently able to do so without such support [10] These lines had normal karyotypes, and they formed teratomas when grown as xenografts. Van de Velde et al [11] were able to obtain pluripotent cell lines from single blastomeres derived from four-cell stage embryos These embryos had been established for this purpose and were of good quality.
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