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Assessing the developmental and malignant potential of human pluripotent stem cells by RNA-seq analysis of Teratomas

ABSTRACT: The International Stem Cell Initiative compared three common approaches for assessing pluripotent stem cells (PSC). The formation of teratomas in vivo, or embryoid bodies (EB) in vitro, provide direct tests of differentiation, whereas PluriTest predicts pluripotency through bioinformatic analysis of transcriptomes of undifferentiated cells. We studied the teratomas by histology and TeratoScore, which analyzes gene expression in each tumor. For the EB assay, we assessed differentiation under neutral conditions and under conditions promoting differentiation to ectoderm, mesoderm, or endoderm lineages. Comparison of each method showed that all assays predict pluripotency, but they have different endpoints that provide different insights. For example, tumors from a subset of lines also contained undifferentiated cells and yolk sac elements that indicate possible malignant potential. This characteristic was not detected by the other two methods. Our results highlight the need for multiple assays to assess both pluripotency and potential malignancy in clinical applications of PSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100223 | GEO | 2017/06/20

SECONDARY ACCESSION(S): PRJNA391086

REPOSITORIES: GEO

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Project description:Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is the trisomy of chromosome 12. Interestingly, trisomy 12 is also prevalent in germ cell tumors (GCTs). Here, we aimed to dissect the cellular and molecular implications of trisomy 12 in hPSCs. A genome-wide gene expression analysis revealed that trisomy 12 profoundly affects the global gene expression profile of hPSCs, inducing a transcriptional program very similar to that of CGTs. Direct comparison of the proliferation, replication, differentiation and apoptosis between diploid and aneuploid hPSCs revealed that trisomy 12 significantly increases the proliferation rate of hPSCs. Increased replication largely accounts for the increased proliferation observed, and may explain the selection advantage that trisomy 12 confers to hPSCs. A comparison of the tumors induced by diploid and aneuploid hPSCs further demonstrated that trisomy 12 increases the tumorigenicity of hPSCs, inducing transcriptionally-distinct teratomas, from which pluripotent cells can be recovered. Lastly, a chemical screen of 89 anticancer drugs against diploid and aneuploid hPSCs discovered that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors, suggesting that the increased proliferation and tumorigenicity of these aberrant cells also makes them more vulnerable, and might potentially be used for their selective elimination from culture. Together, our findings demonstrate the extensive effect of trisomy 12 on the gene expression signature and on the cellular behavior of hPSCs, and highlight the danger posed by this trisomy for the successful use of hPSCs in basic research and in regenerative medicine. Expression data from diploid and aneuoploid human pluripotent stem cells, teratomas derived from them, and pluripotent-like cells recovered from these teratomas total RNA was isolated from undifferentiated human pluripotent stem cells grown under standard human ES conditions, or from teratomas derived from them, or from ES-like cells recovered from these teratomas.

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Assessing the developmental and malignant potential of human pluripotent stem cells by RNA-seq analysis of Teratomas

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