Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from human pluripotent stem cells and differentiated cells treated with pluripotent-specific inhibitors

ABSTRACT: The use of human pluripotent stem cells (hPSCs) in cell therapy is hindered by the tumorigenic risk from residual undifferentiated cells. Here we performed a high-throughput screen of over 52,000 small molecules, and identified 15 highly selective cytotoxic inhibitors of hPSCs (PluriSIns). Cellular and molecular analyses revealed that the most selective compound, PluriSIn #1, is a pluripotent-specific inhibitor of stearoyl-coA desaturase (SCD1), the key enzyme in the biosynthesis of monounsaturated fatty acids (MUFA). SCD1 inhibition in hPSCs induced ER stress, protein synthesis attenuation, and apoptosis of these cells, revealing that MUFA biosynthesis is crucial for their survival. PluriSIn #1 was also cytotoxic toward the ICM cells of mouse embryos, indicating that the dependence on SCD1 is inherent to the pluripotent state. Finally, application of PluriSIn #1 prevented teratoma formation from tumorigenic undifferentiated cells. Our novel method to eliminate undifferentiated cells from culture should thus increase the safety of hPSC-based treatments. Expression data from undifferentiated and differentiated human embryonic stem cells. Total RNA was isolated from undifferentiated human pluripotent stem cells grown on matrigel with mTeSR1 medium, or from early endodermal progenitor cells differentiated from human embryonic stem cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Uri Ben-David

PROVIDER: E-GEOD-37040 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen.

Ben-David Uri U Gan Qing-Fen QF Golan-Lev Tamar T Arora Payal P Yanuka Ofra O Oren Yifat S YS Leikin-Frenkel Alicia A Graf Martin M Garippa Ralph R Boehringer Markus M Gromo Gianni G Benvenisty Nissim N

Cell stem cell 20130111 2

The use of human pluripotent stem cells (hPSCs) in cell therapy is hindered by the tumorigenic risk from residual undifferentiated cells. Here we performed a high-throughput screen of over 52,000 small molecules and identified 15 pluripotent cell-specific inhibitors (PluriSIns), nine of which share a common structural moiety. The PluriSIns selectively eliminated hPSCs while sparing a large array of progenitor and differentiated cells. Cellular and molecular analyses demonstrated that the most se ...[more]

PMID: 23318055

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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.

Dataset Information

Expression data from human pluripotent stem cells and differentiated cells treated with pluripotent-specific inhibitors

Publications

Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen.

Similar Datasets

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