Cell Stem Cell, published online 9 January 2013; doi:10.1016/j.stem.2012.11.015

Hopes for regenerative medicine derive in part from pluripotent stem cells; however, these cells also have tumorigenic properties that limit their use in medicine. Mechanisms to eliminate residual pluripotent stem cells for clinical applications are therefore needed to overcome this limitation. Ben-David et al. now perform a high-throughput small-molecule screen and a smaller-scale counterscreen to identify 15 compounds that are selectively cytotoxic to pluripotent cells. Interestingly, nine of the compounds shared a common phenylhydrazine moiety, and therefore the authors anticipated the molecules might share a common mechanism of action. Gene expression changes resulting from exposure to one compound were consistent with an endoplasmic reticulum stress phenotype. In prior work, this compound, as well as three of the others, scored positive as inhibitors of stearoyl-CoA-desaturase (SCD1), an endoplasmic reticulum membrane protein. Biochemical assays confirmed inhibition of SCD1 in pluripotent stem cells by these compounds. Genetic or chemical disruption of SCD1 activity in stem cells yielded massive cell death, whereas exogenously added oleic acid—the product of SCD1—rescued cells from death, confirming the importance of this enzyme for cell survival. Collectively, these data indicate that pluripotent cells depend on SCD1 activity and suggest that inhibition of SCD1 to eliminate residual pluripotent cells may reduce the risk of tumor formation from stem cell–derived therapeutics.