title: Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen.
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.
authors: Stem Cell Unit, The Hebrew University, Jerusalem 91904, Israel.
authors: Uri
authors: U
authors: Ben-David
authors: Qing-Fen
authors: QF
authors: Gan
authors: Tamar
authors: T
authors: Golan-Lev
authors: Payal
authors: P
authors: Arora
authors: Ofra
authors: O
authors: Yanuka
authors: Yifat S
authors: YS
authors: Oren
authors: Alicia
authors: A
authors: Leikin-Frenkel
authors: Martin
authors: M
authors: Graf
authors: Ralph
authors: R
authors: Garippa
authors: Markus
authors: M
authors: Boehringer
authors: Gianni
authors: G
authors: Gromo
authors: Nissim
authors: N
authors: Benvenisty
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D019301:Oleic Acid / Q000138:chemical synthesis*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D019301:Oleic Acid; D013230:Stearoyl-CoA Desaturase