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Cell Stem Cell. 2013 Feb 7;12(2):167-79. doi: 10.1016/j.stem.2012.11.015. Epub 2013 Jan 11.

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

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1
Stem Cell Unit, The Hebrew University, Jerusalem 91904, Israel.

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 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 selective compound, PluriSIn #1, induces ER stress, protein synthesis attenuation, and apoptosis in hPSCs. Close examination identified this molecule as an inhibitor of stearoyl-coA desaturase (SCD1), the key enzyme in oleic acid biosynthesis, revealing a unique role for lipid metabolism in hPSCs. PluriSIn #1 was also cytotoxic to mouse blastocysts, indicating that the dependence on oleate is inherent to the pluripotent state. Finally, application of PluriSIn #1 prevented teratoma formation from tumorigenic undifferentiated cells. These findings should increase the safety of hPSC-based treatments.

PMID:
23318055
DOI:
10.1016/j.stem.2012.11.015
[Indexed for MEDLINE]
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